N-myristoyl transferase inhibitors

ABSTRACT

The present invention relates to N-heterocyclic sulphonamide compounds, in particular pyrazole sulphonamide compounds, and their use as N-myristoyl transferase inhibitors.

FIELD OF THE INVENTION

The present invention relates to compounds and their use as N-myristoyltransferase inhibitors.

BACKGROUND TO THE INVENTION

The modification of proteins by myristoylation is required for thesubcellular targeting, protein conformation and biological activity ofmany important proteins in eukaryotic cells, including those requiredfor signal transduction and regulatory functions important in cellgrowth (Towler et al. J Biol Chem 1987; 262:1030-6. 20: Wolven et al.Mol Biol Cell 1997; 8:1159-73). The myristoylation reaction, thetransfer of myristic acid from myristoyl-coenzyme A (CoA) to the aminogroups of terminal glycine residues, is catalysed by the ubiquitouslydistributed enzyme N-myristoyl-CoA:protein, N-myristoyl transferase(NMT). The reaction requires only myristoyl-CoA and a protein containinga suitable peptide sequence, and occurs through an ordered Bi Bimechanism. This modification occurs primarily as a cotranslationalprocess (Wilcox et al. Science 1987, 238:1275-8. 22; Deichaite et al.Mol Cell Biol 1988; 8:4295-301), although myristoylation can also occurpost-translationally (Pillai et al. Proc Natl Acad Sci USA 1987;84:7654-8. 24: King et al. J Biol Chem 1989; 264:7772-5).

N-myristoyltransferase (NMT) has been shown to be essential in thekinetoplastid protozoan parasites, Leishmania, Trypanosoma brucei andPlasmodium-falciparum. The demonstration of essentiality by geneticstudies in these parasites has been supported by limited chemicalvalidation. Non-specific myristoyl CoA inhibitors inhibit T. brucei andLeishmania growth in culture. A screen of compounds developed asinhibitors of fungal NMT identified a number of inhibitors of both T.brucei NMT and T. brucei in culture. Screening of recombinant Plasmodiumfalciparum NMT has identified a series of benzothiazole analogues withIC₅₀ values <50 μM, with selectivity over human NMT1. Two of compoundsof the series when tested at a concentration of 10 μM against culturedparasites in vitro reduced parasitemia by >80%. (Bowyer et al.,Biochemical Journal (2007), 408(2), 173-180.)

Two isozymes of the mammalian NMT enzymes, NMT1 and NMT2, have beencloned and share ˜77% identity (Giang D K, Cravatt B F. A secondmammalian N-myristoyltransferase. J Biol Chem 1998; 273:6595-8.) withthe majority of divergence occurring in the amino-terminal domains.Splice variants of NMT1 have also been observed in some cells. Possiblythese amino-terminal variations allow differential cellular localizationof the isozymes, thereby allowing either cotranslational ribosome-basedor post-translational cytosol-based protein myristoylation. NMT1 andNMT2 have similar, but distinguishable, relative selectivity, as shownby an in vitro comparison of the activity of the isozymes on a limitedpanel of substrate peptides. (Giang and Cravatt, J Biol Chem 1998;273:6595-8. 27; Aitken A, Biochem Soc Trans 1989; 17:871-5.).

The role of myristoylation is still being elucidated; however evidenceof its involvement in many disease states, such as cancer (Selvakumar,P. et al., Progress in Lipid Res., 2006, (46), 1-36), epilepsy(Selvakhumar, P. et al., Biochem. Biophys Res. Comm. 2005, (335),1132-1139), Alzheimer's disease, ischemia, diabetes, HIV (Shoji, S. etal., JP2006223173) and osteoporosis is growing. Cellular myristoylatedproteins have diverse biological functions in oncogenesis and signaltransduction. Examples include the catalytic subunit of cAMP4-dependentprotein kinase, various tyrosine kinases (pp60src, pp60yes, pp56lck,pp59fyn/syn, and c-Abl), the α-subunit of calcineurin (Lakshmikuttyamma,A et al., Progress in Neurobiol. 2008, 84 (1), 77-84) the myristoylatedalanine-rich C kinase substrate, and the α-subunit of several guaninenucleotide binding proteins and ADP ribosylation factors.

An increase in NMT activity and expression has been shown in a number oftumour types, suggesting inhibitors of NMT would be potentialanti-cancer agents. In addition the Src family of tyrosine kinases(e.g., c-Src, Yes, and Fyn) are oncogenic proteins which requiremyristoylation in order for them to function in cells.

Functionally characterization of the two NMT isozymes in human cellsusing unique small interfering RNAs (siRNA) for each isozyme were shownto decrease NMT1 or NMT2 protein levels by at least 90%. Knockdown ofNMT1 inhibited cell replication associated with a loss of activation ofc-Src and its target FAK. Depletion of either NMT isozyme inducedapoptosis, with NMT2 having a 2.5-fold greater effect than NMT1.Intratumoral injection of siRNA for NMT1 or for both NMT1 and NMT2inhibited tumour growth in vivo, whereas the same treatment with siRNAfor NMT2 or negative control siRNA did not. Overall, the data indicatethat NMT1 and NMT2 have only partially overlapping functions and thatNMT1 is critical for tumour cell proliferation. (Ducker et al., MolCancer Res 2005; 3(8). August 2005).

Viruses and bacteria usually lack N-myristoyltransferases soconsequently their proteins are processed by NMTs of their eukaryotichosts. (Maurer-Stroh et al., Trends in Microbiology (2004), 12(4),178-185.) For example, human N-myristoyltransferase (hNMT) catalyzesN-myristoylation of several HIV-1 proteins, including Pr160gag-pol,Pr55gag, the capsid protein p17 derived from proteolytic processing ofgag, and neg. factor (nef). N-myristoylation of Pr160gag-pol and Pr55gagis required for viral replication. Reduction in the mRNA levels of humanNMT isoforms and NMT activities have been shown in the course of HIV-1infection in the human T-cell line, CEM. In consequence, novel syntheticNMT inhibitors were significantly more cytotoxic to chronically HIV-1infected T-cell line, CEM/LAV-1, compared to uninfected CEM cells.(Takamune et al., FEBS Letters (2002), 527(1-3), 138-142.)

Myristic acid analogues designed as alternative substrates for NMT haveshown to inhibit the proliferation of HIV-1 (Bryant et al., Perspectivesin Drug Discovery and Design (1993), 1(1), 193-209.; Devadas et al.,Bioorganic & Medicinal Chemistry Letters (1993), 3(4), 779-84.) andHepatitis B (Parang et al., Antiviral Research (1997), 34(3), 75-90.) Inaddition myristic acid analogues have been shown to inhibit HIV-1 (Adamset al., Eur. Pat. Appl. (1992), 20 pp. EP 480901 A1) and VaricellaZoster virus replication (Gilbert et al., Antiviral Chemistry &Chemotherapy (1994), 5(3), 182-6.).

NMT has been shown genetically to be essential for a number of fungalstrains, such as Candida albicans (Weinberg et al., MolecularMicrobiology (1995), 16(2), 241-50.), Saccharomyces cerevisiae,Cryptococcus neoformans (Lodge et al., PNAS USA (1994), 91(25),12008-12.) and Aspergillus fumigatus (Cook, W J et al., US Patent20020025524 (2002), both in culture and animal models of infection.

Given the diverse role of myristoyl transferases and their associationwith a large variety of diseases and disorders, there is a need to findfurther myristoyl transferase inhibitors.

The present inventors have provided sulphonamide compounds which areinhibitors of N-myristoyl transferases.

STATEMENTS OF THE INVENTION

The present invention relates to a class of N-heterocyclic sulphonamidesand to their use in therapy. More particularly, the invention provides afamily of N-heteroarylsulphonamides which are substituted [in the meta-or para-position] by an optionally substituted amine-bearing moiety.

According to a first aspect of the invention there is provided asulphonamide derivative comprising a sulphonamide group linking aN-heterocyclic head group and tail group via an aryl or heteroaryllinker attached to the tail wherein the tail includes a protonatablemoiety such as a primary, secondary or tertiary alkylamine (or aprotonatable heterocycle such as imidazole).

In a preferred aspect of the invention there is provided a compound offormula (I)

whereinn is 0, 1, 2, 3, 4, 5 or 6;ring A, herein referred to as a “head” group, is an optionallysubstituted nitrogen containing aryl group wherein each substitutablecarbon or nitrogen in Ring A is optionally and independently substitutedby one or more R⁵ and wherein if Ring A contains an —NH— moiety thatnitrogen may be optionally substituted by C₁₋₆ alkyl (e.g. methyl); andwherein R⁴ and ring A together with the atoms to which they are attachedmay form a cyclic group.ring B is an optionally substituted aryl or heteroaryl group whereineach substitutable carbon or heteroatom in Ring B is optionally andindependently substituted by one or more R³;W and X, one of which may be absent, are independently selected fromR¹¹, hydrocarbyl (e.g. C₁₋₈ alkyl, alkenyl, alkynyl, or haloalkyl)optionally substituted with R¹¹, and —(CH₂)_(k)-heterocyclyl optionallysubstituted with R¹²; k is 0, 1, 2, 3, 4, 5 or 6;R¹, R², R³, R⁴ and R⁵ are independently selected from hydrogen, R¹²,hydrocarbyl (e.g. C₁₋₆ alkyl, alkenyl, alkynyl, or haloalkyl) optionallysubstituted with R¹², and —(CH₂)_(i)-heterocyclyl optionally substitutedwith R¹²; wherein R¹ and R² taken together with the atoms to which theyare attached may form a heterocycle, optionally substituted with one ormore R¹²; wherein R¹ and/or R² taken together with W or X may form aheterocycle optionally substituted with one or more R¹²; and wherein oneor more of R³ and R⁵ taken together with the atoms to which they areattached may form a carbocycle, for example heterocyclyl, optionallysubstituted with R¹²; l is 0, 1, 2, 3, 4, 5 or 6;

-   -   wherein each R¹¹ and R¹² is independently selected from halogen,        trifluoromethyl, cyano, thio, nitro, oxo, ═NR¹³, —OR¹³, —SR¹³,        —C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³, —NR¹³COR¹⁴, —NR¹³CONR¹³ ₂,        —NR¹³COR¹⁴, —NR¹³CO₂R¹⁴, —S(O)R¹³, —S(O)₂R¹³, —SONR¹³ ₂,        —NR¹³S(O)₂R¹⁴; —CSR¹³, —N(R¹³)R¹⁴, —C(O)N(R¹³)R¹⁴, —SO₂N(R¹³)R¹⁴        and R¹⁵;    -   wherein R¹³ and R¹⁴ are each independently selected from        hydrogen or R¹⁵;    -   wherein R¹⁵ is selected from hydrocarbyl (e.g. C₁₋₆ alkyl,        alkenyl, alkynyl, or haloalkyl), carbocyclyl and        —(CH₂)_(m)-heterocyclyl, and each R¹⁵ is optionally and        independently substituted with one or more of halogen, cyano,        amino, hydroxy, C₁₋₆ alkyl or cycloalkyl and C₁₋₆ alkoxy;    -   m is 0, 1, 2, 3, 4, 5 or 6;        p is 0, 1, 2, 3 or 4; wherein the values of R⁴ may be the same        or different;        q is 0, 1, 2, 3 or 4; wherein the values of R⁵ may be the same        or different;        or a pharmaceutically acceptable salt or pro-drug thereof.

According to a further aspect of the invention there is provided asulphonamide derivative comprising a sulphonamide group linking aheteroaryl head group and an aryl or heteroaryl central group for use asa medicament.

In a second aspect of the invention there is provided a compound offormula (II) for use as a medicament:

wherein n, ring A, ring B, R³, R⁴, R⁵, p and q are as defined herein;Y and Z, one or both of which may be absent, are independently selectedfrom hydrogen, R¹⁶, hydrocarbyl (e.g. C₁₋₆ alkyl, alkenyl, alkynyl, orhaloalkyl) optionally substituted with R¹⁶, and —(CH₂)_(r)-heterocyclyloptionally substituted with R¹⁶, wherein each R¹⁶ is independentlyselected from halogen, trifluoromethyl, cyano, thio, nitro, oxo, ═NR¹⁷,—OR¹⁷, —SR¹⁷, —C(O)R¹⁷, —C(O)OR¹⁷, —OC(O)R¹⁷, —NR¹⁷COR¹⁸, —NR¹⁷CONR¹⁸ ₂,—NR¹⁷COR¹⁸, —NR¹⁷CO₂R¹⁸, —S(O)R¹⁷, —S(O)₂R¹⁷, —SONR¹⁷ ₂, —NR¹⁷S(O)₂R¹⁸;—CSR¹⁷, —N(R¹⁷)R¹⁸, —C(O)N(R¹⁷)R¹⁸, —SO₂N(R¹⁷)R¹⁸ and R¹⁹; r is 0, 1, 2,3, 4, 5 or 6;

-   -   wherein R¹⁷ and R¹⁸ are each independently selected from        hydrogen or R¹⁹;    -   wherein R¹⁹ is selected from hydrocarbyl (e.g. C₁₋₆ alkyl,        alkenyl, alkynyl, or haloalkyl), carbocyclyl and        —(CH₂)_(s)-heterocyclyl, and each R¹⁹ is optionally and        independently substituted with one or more of halogen, cyano,        amino, hydroxy, C₁₋₆ alkyl and C₁₋₆ alkoxy;    -   s is 0, 1, 2, 3, 4, 5 or 6;        or a pharmaceutically acceptable salt or pro-drug thereof.

Preferably Y is absent and Z is halogen e.g. Br or Cl. Preferably still,ring B is aryl e.g. a 6-membered aromatic ring including benzene.

n may be 0 or 1. Preferably n is 0.

The compounds of the invention can exist in different forms, such asfree acids, free bases, esters and other prodrugs, salts and tautomers,for example, and the invention includes all variant forms of thecompounds.

Hydrocarbyl

The term “hydrocarbyl” as used herein includes reference to moietiesconsisting exclusively of hydrogen and carbon atoms; such a moiety maycomprise an aliphatic and/or an aromatic moiety. The moiety may comprise1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20carbon atoms. Examples of hydrocarbyl groups include C₁₋₆ alkyl (e.g.C₁, C₂, C₃ or C₄ alkyl, for example methyl, ethyl, propyl, isopropyl,n-butyl, sec-butyl or tert-butyl); C₁₋₆ alkyl substituted by aryl (e.g.benzyl) or by cycloalkyl (e.g cyclopropylmethyl); cycloalkyl (e.g.cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl); alkenyl (e.g.2-butenyl); alkynyl (e.g. 2-butynyl); aryl (e.g. phenyl, benzyl,naphthyl or fluorenyl) and the like.

Alkyl

The terms “alkyl” and “C₁₋₆ alkyl” as used herein can be usedinterchangeably and include reference to a straight or branched chainalkyl moiety having 1, 2, 3, 4, 5 or 6 carbon atoms. This term includesreference to groups such as methyl, ethyl, propyl (n-propyl orisopropyl), butyl (n-butyl, iso-butyl, sec-butyl or tert-butyl), pentyl,hexyl and the like. In particular, alkyl may have 1, 2, 3 or 4 carbonatoms. Haloalkyl relates to an alkyl radical preferably having 1 to 8carbon atoms, preferably 1 to 4 carbon atoms, substituted with one ormore halide atoms for example CH₂CH₂Br, CF₃ or CCl₃.

Alkenyl

The terms “alkenyl” and “C₂₋₆ alkenyl” as used herein can be usedinterchangeably and include reference to a straight or branched chainalkyl moiety having 2, 3, 4, 5 or 6 carbon atoms and having, inaddition, at least one double bond, of either E or Z stereochemistrywhere applicable. This term, includes reference to groups such asethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl,2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl and 3-hexenyl and the like.

Alkynyl

The terms “alkynyl” and “C₂₋₆ alkynyl” as used herein can be usedinterchangeably and include reference to a straight or branched chainalkyl moiety having 2, 3, 4, 5 or 6 carbon atoms and having, inaddition, at least one triple bond. This term includes reference togroups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl and3-hexynyl and the like.

Alkoxy

The terms “alkoxy” and “C₁₋₆ alkoxy” as used herein can be usedinterchangeably and include reference to —O-alkyl, wherein alkyl isstraight or branched chain and comprises 1, 2, 3, 4, 5 or 6 carbonatoms. In one class of embodiments, alkoxy has 1, 2, 3 or 4 carbonatoms. This term includes reference to groups such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like.

Cycloalkyl

The term “cycloalkyl” as used herein includes reference to an alicyclicmoiety having 3, 4, 5, 6, 7 or 8 carbon atoms. The group may be abridged or polycyclic ring system. More often cycloalkyl groups aremonocyclic. This term includes reference to groups such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl andthe like.

Aryl

The term “aryl” as used herein includes reference to an aromatic ringsystem comprising 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring carbonatoms. Aryl is often phenyl but may be a polycyclic ring system, havingtwo or more rings, at least one of which is aromatic. This term includesreference to groups such as phenyl, naphthyl, fluorenyl, azulenyl,indenyl, anthryl and the like.

Carbocyclyl

The term “carbocyclyl” as used herein includes reference to a saturated(e.g. cycloalkyl) or unsaturated (e.g. aryl) ring moiety having 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 carbon ring atoms. Inparticular, carbocyclyl includes a 3- to 10-membered ring or ring systemand, in particular, a 5- or 6-membered ring, which may be saturated orunsaturated. A carbocyclic moiety is, for example, selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl,bicyclo[2.2.2]octyl, phenyl, benzyl, naphthyl, fluorenyl, azulenyl,indenyl, anthryl and the like.

Heterocyclyl

The term “heterocyclyl” as used herein includes reference to a saturated(e.g. heterocycloalkyl) or unsaturated (e.g. heteroaryl) heterocyclicring moiety having from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or16 ring atoms, at least one of which is selected from nitrogen, oxygen,phosphorus, silicon and sulphur. In particular, heterocyclyl includes a3- to 10-membered ring or ring system and more particularly a 5- or 6-or 7-membered ring, which may be saturated or unsaturated.

A heterocyclic moiety is, for example, selected from oxiranyl, azirinyl,1,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl,thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl,2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl,imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl,thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl,pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl,morpholinyl, thiomorpholinyl, especially thiomorpholino, indolizinyl,isoindolyl, 3H-indolyl, indolyl, benzimidazolyl, cumaryl, indazolyl,triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl,tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl,octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl,dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl,quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl,p-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl,furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl,isochromanyl, chromanyl and the like.

Heterocycloalkyl

The term “heterocycloalkyl” as used herein includes reference to asaturated heterocyclic moiety having 3, 4, 5, 6 or 7 ring carbon atomsand 1, 2, 3, 4 or 5 ring heteroatoms selected from nitrogen, oxygen,phosphorus and sulphur. The group may be a polycyclic ring system butmore often is monocyclic. This term includes reference to groups such asazetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl,pyrazolidinyl, imidazolyl, indolizidinyl, piperazinyl, thiazolidinyl,morpholinyl, thiomorpholinyl, quinolinidinyl and the like.

Heteroaryl

The term “heteroaryl” as used herein includes reference to an aromaticheterocyclic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or16 ring atoms, at least one of which is selected from nitrogen, oxygenand sulphur. The group may be a polycyclic ring system, having two ormore rings, at least one of which is aromatic, but is more oftenmonocyclic. This term includes reference to groups such as pyrimidinyl,furanyl, benzo[b]thiophenyl, thiophenyl, pyrrolyl, imidazolyl,pyrrolidinyl, pyridinyl, benzo[b]furanyl, pyrazinyl, purinyl, indolyl,benzimidazolyl, quinolinyl, phenothiazinyl, triazinyl, phthalazinyl,2H-chromenyl, oxazolyl, isoxazolyl, thiazolyl, isoindolyl, indazolyl,purinyl, isoquinolinyl, quinazolinyl, pteridinyl and the like.

Halogen

The term “halogen” as used herein includes reference to F, Cl, Br or I.In particular, halogen may be F or Cl.

Substituted

The term “substituted” as used herein in reference to a moiety meansthat one or more, especially up to 5, more especially 1, 2 or 3, of thehydrogen atoms in said moiety are replaced independently of each otherby the corresponding number of the described substituents. The term“optionally substituted” as used herein means substituted orunsubstituted.

It will, of course, be understood that substituents are only atpositions where they are chemically possible, the person skilled in theart being able to decide (either experimentally or theoretically)without inappropriate effort whether a particular substitution ispossible. For example, amino or hydroxy groups with free hydrogen may beunstable if bound to carbon atoms with unsaturated (e.g. olefinic)bonds. Additionally, it will of course be understood that thesubstituents described herein may themselves be substituted by anysubstituent, subject to the aforementioned restriction to appropriatesubstitutions as recognised by the skilled man.

Independently

Where two or more moieties are described as being “each independently”selected from a list of atoms or groups, this means that the moietiesmay be the same or different. The identity of each moiety is thereforeindependent of the identities of the one or more other moieties.

Ring A is preferably an optionally substituted 5 or 6 membered nitrogencontaining heteroaryl. For example, ring A may be an optionallysubstituted 5 membered nitrogen-containing heteroaryl including, but notlimited to, optionally substituted pyrazole, imidazole, imidazoline,triazole or tetrazole. Alternatively ring A may be an optionallysubstituted 6 membered nitrogen-containing heteroaryl including, but notlimited to, optionally substituted pyridine, 3 amino pyridine, 4 aminopyridine, pyridazine, pyrimidine, pyrazine, triazine and tetrazine.

Ring A may be Comprise other ring heteroatoms in addition to N forexample O or S. For example ring A may be optionally substitutedisoxazole.

Preferably ring A is selected from optionally substituted pyrazole,pyridine or isoxazole.

Preferably still ring A is optionally substituted pyrazole. Thus in apreferred aspect of the invention there is provided a compound offormula (III)

wherein n, ring B, W, X, R¹, R², R³, R⁴, R⁵, p and q are as definedherein.

In a further preferred aspect of the invention there is provided acompound of formula (III)(i)

wherein n, ring B, W, X, R¹, R², R³, R⁴, p and q are as defined hereinand R^(5a), R^(5b) and R^(5c) are independently selected from hydrogen,R¹², hydrocarbyl (e.g. C₁₋₆ alkyl, alkenyl, alkynyl, or haloalkyl)optionally substituted with R¹², and —(CH₂)_(i)-heterocyclyl optionallysubstituted with R¹².

In one embodiment, there is provided a compound of formula (III)(i)wherein R^(5a) is C₁₋₆ alkyl (e.g. methyl).

Preferably ring B is an optionally substituted 5 or 6 membered aryl(e.g. benzene) or heteroaryl wherein each substitutable carbon orheteroatom in ring B may be optionally and independently substituted byhalogen for example selected from one or more of F, CI and Br. Ring Bmay be a 5 membered aryl containing one or more heteroatoms selectedfrom N, S and O. By way of example ring B may be thiophene.Alternatively ring B may be a 6 membered aryl containing one or moreheteratoms selected from N, S and O. By way of example ring B may be a 6membered nitrogen containing heteroaryl, for example pyridine.

Thus there may be provided a compound of formula IV

wherein n, ring A, W, X, R¹, R², R³, R⁴, R⁵, p and q are as definedherein; and E is independently selected from C and N.

In one embodiment the invention provides a compound of formula (IV)wherein E is N.

In another embodiment the invention provides a compound of formula (IV)wherein E is C.

In a preferred aspect of the invention there is provided a compound offormula (IV)(i)

wherein n, W, X, R¹, R², R³, R⁴, R⁵, p and q are as defined herein; andE is independently selected from C and N.

In a further preferred aspect of the invention there is provided acompound of formula (IV)(ii)

wherein n, W, X, R¹, R², R⁴, R⁵, p and q are as defined herein; andwherein R^(3a), R^(3b), R^(3c) and R^(3d) are independently selectedfrom hydrogen, R¹², hydrocarbyl (e.g. C₁₋₆ alkyl, alkenyl, alkynyl, orhaloalkyl) optionally substituted with R¹², and —(CH₂)_(i)-heterocyclyloptionally substituted with R¹².

Preferably, R^(3a), R^(3b), R^(3c) and R^(3d) are independently selectedfrom hydrogen, halogen (e.g. Cl or F) and C₁₋₆ alkyl or haloalkyl.

In a further preferred aspect of the invention there is provided acompound of formula (IV)(iii)

Preferably R^(3a) and/or R^(3b) is halogen for example Cl or F.

In a preferred aspect of the invention W is absent and X is carbocyclyle.g. heterocyclyl optionally substituted with R¹¹. Preferably X is aryl,for example heteroaryl, or heterocyclyl optionally substituted with R¹¹.

In one embodiment of the invention, W is aryl optionally substitutedwith R¹¹ and X is C₁₋₆ alkyl, e.g. CH₂.

Preferably R¹ and R² are joined with N to form a saturated five to sevenmembered protonatable N-containing heterocycle, for example piperidine,azepane or azocane, optionally substituted with one or more R¹².

Preferably at least one of R¹ or R² is an amine. Preferably still R¹ andR², wherein one of R¹ or R² is an amine, are joined with N to form aprotonatable N containing heterocycle for example piperazine, optionallysubstituted with one or more R¹².

Preferably R⁴ is selected from hydrogen or C₁₋₆ alkyl optionallysubstituted with halogen, cyano, amino, hydroxy, C₁₋₆ alkyl and C₁₋₆alkoxy or carbocyclyl, for example cycloalkyl or aryl. The inventorshave found that substitution of the sulphonamide nitrogen atom enhancespenetration of the compounds into the mouse CNS. Thus, preferably stillR⁴ is C₁₋₆ alkyl e.g. methyl or C₁₋₆ alkyl substituted with fluoro e.g.monofluoroalkyl, difluoroalkyl or trifluoroalkyl.

Preferably R⁵ is selected from hydrogen and C₁₋₆ alkyl e.g. methyl.

The invention further provides a compound of formula V

wherein n, ring A, W, ring B, R³, R⁴, R⁵, p and q are as defined herein;t is 0, 1, 2, 3, 4, 5 or 6; ring D is an optionally substituted nitrogencontaining 6 or 7 membered heterocycle, for example piperidine, whereineach substitutable carbon or nitrogen in Ring D is optionally andindependently substituted by one or more R⁷; R⁷ is independentlyselected from hydrogen, R²⁰, hydrocarbyl (e.g. C₁₋₆ alkyl, alkenyl,alkynyl, or haloalkyl) optionally substituted with R²⁰, and—(CH₂)_(v)-heterocyclyl optionally substituted with R²⁰; v is 0, 1, 2,3, 4, 5 or 6;

-   -   wherein each R²⁰ is independently selected from halogen,        trifluoromethyl, cyano, thio, nitro, oxo, ═NR²¹, —OR²¹, —SR²¹,        —C(O)R²¹, —C(O)OR²¹, —OC(O)R²¹, —NR²¹COR²², —NR²¹CONR²² ₂,        —NR²¹COR²², —NR²¹CO₂R²², —S(O)R²¹, —S(O)₂R²¹, —SONR²¹ ₂,        —NR²¹S(O)₂R²²; —CSR²¹, —N(R²¹)R²², —C(O)N(R²¹)R²², —SO₂N(R²¹)R²²        and R²³;    -   wherein R²¹ and R²² are each independently selected from        hydrogen or R²³;    -   wherein R²³ is selected from hydrocarbyl (e.g. C₁₋₆ alkyl,        alkenyl, alkynyl, or haloalkyl), carbocyclyl and        —(CH₂)_(w)-heterocyclyl, and each R²³ is optionally and        independently substituted with one or more of halogen, cyano,        amino, hydroxy, C₁₋₆ alkyl and C₁₋₆ alkoxy;    -   w is 0, 1, 2, 3, 4, 5 or 6;

R⁸ is selected from the list of optional substituents represented by thegroup R⁴.

Preferably R⁸ is hydrogen or methyl. Preferably still R⁸ is methyl.

Preferably W is C₁₋₈ alkyl, in particular C₁₋₆ alkyl, optionallysubstituted with oxo.

In a preferred aspect of the invention there is provided a compound offormula (V)(i)

wherein ring D, E, n, R³, R⁴, R⁵, R⁷, R⁸, p, q and t are as definedherein; n′ is 0, 1, 2, 3, 4, 5, 6, 7 or 8. Preferably E is C.

The invention further provides a compound of formula VI

wherein n, ring A, W, ring B, R³, R⁴, R⁵, R⁷, R⁸, p, q and t are asdefined herein; ring D is an optionally substituted nitrogen containing6 or 7 membered heterocycle, for example 1,4-piperazine, wherein eachsubstitutable carbon or nitrogen in Ring D is optionally andindependently substituted by one or more R⁷.

In one embodiment the invention provides a compound of formula (VI)wherein W is cycloalkyl, for example heterocycloalkyl such aspiperidinyl.

In one embodiment of the invention there is provided a compound offormula VI wherein W is C₁₋₆ alkyl for example propyl.

Preferably ring B is a benzene ring or pyridinyl. Thus, in a preferredaspect the invention provides a compound of formula (VI)(i)

wherein n, n′, ring D, E, R³, R⁴, R⁵, R⁷, R⁸, p, q and t are as definedherein. Preferably E is C.

In a preferred compound of the invention W is an optionally substitutedaryl or heteroaryl group. Thus in a further preferred aspect of theinvention there is provided a compound of formula VII

wherein n, ring A, ring B, ring D, R³, R⁴, R⁵, R⁷, R⁸, p, q and t are asdefined herein; u is 0, 1, 2, 3, 4, 5 or 6; ring C is an optionallysubstituted cyclic group wherein each substitutable carbon or heteroatomin Ring C is optionally and independently substituted by one or more R⁶;R⁶ is independently selected from hydrogen, R²⁰, hydrocarbyl (e.g. C₁₋₆alkyl, alkenyl, alkynyl, or haloalkyl) optionally substituted with R²⁰,and —(CH₂)_(v)-heterocyclyl optionally substituted with R²⁰; v is 0, 1,2, 3, 4, 5 or 6;

-   -   wherein each R²⁰ is independently selected from halogen,        trifluoromethyl, cyano, thio, nitro, oxo, ═NR²¹, —OR²¹, —SR²¹,        —C(O)R²¹, —C(O)OR²¹, —OC(O)R²¹, —S(O)R²¹, —S(O)₂R²¹, —N(R²¹)R²²,        —C(O)N(R²¹)R²², —SO₂N(R²¹)R²² and R²³;    -   wherein R²¹ and R²² are each independently selected from        hydrogen or R²³;    -   wherein R²³ is selected from hydrocarbyl (e.g. C₁₋₆ alkyl,        alkenyl, alkynyl, or haloalkyl), carbocyclyl and        —(CH₂)_(w)-heterocyclyl, and each R²³ is optionally and        independently substituted with one or more of halogen, cyano,        amino, hydroxy, C₁₋₆ alkyl and C₁₋₆ alkoxy;    -   w is 0, 1, 2, 3, 4, 5 or 6;        n′ is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

In one embodiment of the invention there is provided a compound offormula VII wherein ring B and Ring C are aryl.

In a preferred aspect, the invention provides a compound of formulaVII(i)

wherein n, n′, ring C, ring D, E, R³, R⁴, R⁵, R⁶, R⁷, R⁸, p, q, t and uare as defined herein. Preferably E is C.

Ring C may be a carbocycle, for example aryl. Alternatively ring C maybe a heterocycle for example heterocycloalkyl (e.g. piperidinyl) orheteroaryl. Preferably ring C is aryl (e.g. phenyl) or heteroaryl(pyridinyl).

Preferably ring D is 6 or 7 membered heterocycle, for example, a 6membered heterocycle. Preferably ring D is a saturated heterocycle. Byway of example, ring D may be an optionally substituted pyrrolidine,pyrazolidine, imidazolidine, piperidine or piperazine (e.g.1,4-piperazine). Alternatively, ring D may be an unsaturated heterocyclefor example an optionally substituted pyyrole, pyrazole, imidazole,imidazoline, pyridine, pyrazine, pyrimidine or triazine. Preferablystill, ring D is an optionally substituted imidazole.

Thus in a further preferred aspect of the invention there is provided acompound of formula VIII

wherein n, n′, ring A, ring B, ring D, R³, R⁴, R⁵, R⁷, R⁸, p, q and tare as defined herein; G is independently selected from C and N.

In one embodiment there is provided a compound of formula VIII wherein Gis C. In an alternative embodiment there is provided a compound offormula VIII wherein G is N.

In a preferred aspect of the invention, ring D is selected frompiperidin-4-yl, 1-methyl piperidin-4-yl, piperidin-3-yl, 1-methylpiperidin-3-yl, piperidin-2-yl, 1-methyl piperidin-2-yl,piperazine-4-yl, 1-methyl piperazine-4-yl, 1,4-homopiperazine-4-yl,1-methy-1,4-homopiperazin-4-yl, 1-methyl pyrolidin-3-yl, 1-methylpyrolidin-2-yl, imidazol-1-yl, imidazol-2-yl, quinuclidin-3-yl,quinuclidin-4-yl.

The invention further provides a compound of formula IX(a)

wherein n, n′, E, X, R³, R⁴, R⁵, p and q are as defined herein andwherein J is independently a nitrogen containing heterocycle, forexample heteroaryl, or an amine. Preferably E is C.

J may be selected from piperidin-4-yl, 1-methyl piperidin-4-yl,piperidin-3-yl, 1-methyl piperidin-3-yl, piperidin-2-yl, 1-methylpiperidin-2-yl, piperazine-4-yl, 1-methyl piperazine-4-yl,1,4-homopiperazine-4-yl, 1-methy-1,4-homopiperazin-4-yl, 1-methylpyrolidin-3-yl, 1-methyl pyrolidin-2-yl, imidazol-1-yl, imidazol-2-yl,quinuclidin-3-yl, quinuclidin-4-yl. Alternatively J may be selected from—NH₂, a secondary amine of formula —NHR and a tertiary amine of formula—NRR′, where R and R′ are independently C₁₋₆ alkyl optionallysubstituted with halogen, cyano, amino, hydroxy, C₁₋₆ alkyl and C₁₋₆alkoxy or carbocyclyl, for example cycloalkyl or aryl

Preferably R⁴ is C₁₋₆ alkyl optionally substituted with halogen, cyano,amino, hydroxy, C₁₋₆ alkyl and C₁₋₆ alkoxy or carbocyclyl, for examplecycloalkyl or aryl. Preferably R³ is chloro, fluoro or methyl.Preferably n′ is 0, 1 or 2. Preferably X is oxygen or C₁₋₆ alkyl e.g.CH₂.

The present invention further provides a compound according to theinvention which comprises the racemate, the S or the R enantiomer or amixture thereof, of a compound according to the invention. Preferably,the compound is the S-enantiomer or the R-enantiomer.

Illustrative, but non-limiting, examples of the compounds, includingpharmaceutically acceptable salts thereof, of the present invention areshown in Table 1.

Preferred examples of compounds of the invention include DDD85646,DDD86481, DD99742, DDD99837, DDD100097, DDD100144, DDD100153, DDD100156,DDD100159, DDD100160, DDD100161 and DDD100868 as shown in Table 1.

Further preferred examples of compounds of the invention includeDD99742, DDD100097, DDD100144, DDD100153 as shown in Table 1. Analternative preferred example of a compound of the invention isDDD85646.

Several methods for preparing the compounds of the invention areillustrated in the Schemes shown in the Examples (starting materials aremade according to procedures known in the art or as illustrated herein).Thus in a further aspect of the invention there is provided a processfor the manufacture of any one or more of the compounds according to thefirst aspect of the invention. Thus the invention provides a process forthe preparation of a compound of formula I comprising the reaction stepsof Example 1.

Any mixtures of final products or intermediates obtained can beseparated on the basis of the physico-chemical differences of theconstituents, in a known manner, into the pure final products orintermediates, for example by chromatography, distillation, fractionalcrystallisation, or by the formation of a salt if appropriate orpossible under the circumstances.

Compounds of the invention may be in the form of salts. In particular,the salts may be pharmaceutically acceptable salts. The pharmaceuticallyacceptable salts of the present disclosure can be synthesized from theparent compound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., US, 1985, p. 1418, thedisclosure of which is hereby incorporated by reference; see also Stahlet al, Eds, “Handbook of Pharmaceutical Salts Properties Selection andUse”, Verlag Helvetica Chimica Acta and Wiley-VCH, 2002.

The disclosure thus includes pharmaceutically-acceptable salts of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. For example the conventional non-toxic saltsor the quaternary ammonium salts which are formed, e.g. from inorganicor organic acids or bases. Examples of such acid addition salts includeacetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, tosylate, and undecanoate. Base salts includeammonium salts, alkali metal salts such as sodium and potassium salts,alkaline earth metal salts such as calcium and magnesium salts, saltswith organic bases such as dicyclohexylamine salts,N-methyl-D-glucamine, and salts with amino acids such as arginine,lysine, and so forth. Also, the basic nitrogen-containing groups may bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethyl bromidesand others.

The invention includes prodrugs for the active pharmaceutical species ofthe invention, for example in which one or more functional groups areprotected or derivatised but can be converted in vivo to the functionalgroup, as in the case of esters of carboxylic acids convertible in vivoto the free acid, or in the case of protected amines, to the free aminogroup. The term “prodrug,” as used herein, represents in particularcompounds which are rapidly transformed in vivo to the parent compound,for example, by hydrolysis in blood. A thorough discussion is providedin T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, Edward B. Roche, ed., BioreversibleCarriers in Drug Design, American Pharmaceutical Association andPergamon Press, 1987; H Bundgaard, ed, Design of Prodrugs, Elsevier,1985; and Judkins, et al. Synthetic Communications, 26(23), 4351-4367(1996), each of which is incorporated herein by reference.

Also to be mentioned as metabolic activations of prodrugs are nucleotideactivation, phosphorylation activation and decarboxylation activation.For additional information, see “The Organic Chemistry of Drug Designand Drug Action”, R B Silverman (particularly Chapter 8, pages 497 to546), incorporated herein by reference.

The use of protecting groups is fully described in ‘Protective Groups inOrganic Chemistry’, edited by J W F McOmie, Plenum Press (1973), and‘Protective Groups in Organic Synthesis’, 2nd edition, T W Greene & P GM Wutz, Wiley-Interscience (1991).

Thus, it will be appreciated by those skilled in the art that, althoughprotected derivatives of compounds of the disclosure may not possesspharmacological activity as such, they may be administered, for exampleparenterally or orally, and thereafter metabolised in the body to formcompounds of the invention which are pharmacologically active. Suchderivatives are therefore examples of “prodrugs”. All prodrugs of thedescribed compounds are included within the scope of the disclosure.

Some groups mentioned herein (especially those containing heteroatomsand conjugated bonds) may exist in tautomeric forms and all thesetautomers are included in the scope of the disclosure. More generally,many species may exist in equilibrium, as for example in the case oforganic acids and their counterpart anions; a reference herein to aspecies accordingly includes reference to all equilibrium forms thereof.

The compounds of the invention may also contain one or more asymmetriccarbon atoms and may therefore exhibit optical and/ordiastereoisomerism. All diastereoisomers may be separated usingconventional techniques, e.g. chromatography or fractionalcrystallisation. The various stereoisomers may be isolated by separationof a racemic or other mixture of the compounds using conventional, e.g.fractional crystallisation or HPLC, techniques. Alternatively thedesired optical isomers may be made by reaction of the appropriateoptically active starting materials under conditions which will notcause racemisation or epimerisation, or by derivatisation, for examplewith a homochiral acid followed by separation of the diastereomericderivatives by conventional means (e.g. HPLC, chromatography oversilica). All stereoisomers are included within the scope of thedisclosure. Where a single enantiomer or diasteromer is disclosed, thedisclosure also covers the other enantiomers or diastereomers, and alsoracemates; in this regard, particular reference is made to the specificcompounds listed herein.

Geometric isomers may also exist in the compounds of the presentdisclosure. The present disclosure contemplates the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon-carbon double bond and designates suchisomers as of the Z or E configuration, wherein the term “Z” representssubstituents on the same side of the carbon-carbon double bond and theterm “E” represents substituents on opposite sides of the carbon-carbondouble bond.

The disclosure therefore includes all variant forms of the definedcompounds, for example any tautomer or any pharmaceutically acceptablesalt, ester, acid or other variant of the defined compounds and theirtautomers as well as substances which, upon administration, are capableof providing directly or indirectly a compound as defined above orproviding a species which is capable of existing in equilibrium withsuch a compound.

Pharmaceutical Formulations and Use

The compounds of the invention in free form or in pharmaceuticallyacceptable salt form possess pharmacological activity. They aretherefore intended for use as a pharmaceutical. In particular theyinhibit N-myristoyl transferase activity.

Where used in therapy, the compounds of the invention will normally beadministered orally, intravenously, subcutaneously, buccally, rectally,dermally, nasally, tracheally, bronchially, by any other parenteralroute, as an oral or nasal spray or via inhalation, The compounds may beadministered in the form of pharmaceutical preparations comprisingprodrug or active compound either as a free compound or, for example, apharmaceutically acceptable non-toxic organic or inorganic acid or baseaddition salt, in a pharmaceutically acceptable dosage form. Dependingupon the disorder and patient to be treated and the route ofadministration, the compositions may be administered at varying doses.

Typically, therefore, the pharmaceutical compounds of the invention maybe administered orally or parenterally (“parenterally” as used herein,refers to modes of administration which include intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous andintraarticular injection and infusion) to a host to obtain an inhibitoryeffect. In the case of larger animals, such as humans, the compounds maybe administered alone or as compositions in combination withpharmaceutically acceptable diluents, excipients or carriers.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions, and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required for toachieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved.

In the treatment, prevention, control, amelioration, or reduction ofrisk of conditions which require inhibition of kinase activity, anappropriate dosage level will generally be about 0.01 to 500 mg per kgpatient body weight per day which can be administered in single ormultiple doses. Preferably, the dosage level will be about 0.1 to about250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.A suitable dosage level may be about 0.01 to 250 mg/kg per day, about0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within thisrange the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.For oral administration, the compositions are preferably provided in theform of tablets containing 1.0 to 1000 milligrams of the activeingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0,100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0,900.0 and 1000.0 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. The compounds maybe administered on a regimen of 1 to 4 times per day, preferably once ortwice per day. The dosage regimen may be adjusted to provide the optimaltherapeutic response.

According to a further aspect of the invention there is thus provided apharmaceutical composition including a compound of the invention, inadmixture with a pharmaceutically acceptable adjuvant, diluent orcarrier.

Pharmaceutical compositions of this invention for parenteral injectionsuitably comprise pharmaceutically acceptable sterile aqueous ornonaqueous solutions, dispersions, suspensions or emulsions as well assterile powders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), and suitable mixtures thereof, vegetable oils(such as olive oil) and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservative,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben, chlorobutanolor phenol sorbic acid. It may also be desirable to include isotonicagents such as sugars or sodium chloride, for example. Prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents (for example aluminum monostearate and gelatin)which delay absorption.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are suitably made by forming microencapsulematrices of the drug in biodegradable polymers, for examplepolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations may also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues. The injectableformulations can be sterilized, for example, by filtration through abacterial-retaining filter or by incorporating sterilizing agents in theform of sterile solid compositions which can be dissolved or dispersedin sterile water or other sterile injectable media just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound is typically mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier such as sodium citrate or dicalciumphosphate and/or one or more: a) fillers or extenders such as starches,lactose, sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents. Solid compositions of a similar type mayalso be employed as fillers in soft and hard-filled gelatin capsulesusing such excipients as lactose or milk sugar as well as high molecularweight polyethylene glycol, for example.

Suitably, oral formulations contain a dissolution aid. The dissolutionaid is not limited as to its identity so long as it is pharmaceuticallyacceptable. Examples include nonionic surface active agents, such assucrose fatty acid esters, glycerol fatty acid esters, sorbitan fattyacid esters (e.g. sorbitan trioleate), polyethylene glycol,polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fattyacid esters, polyoxyethylene alkyl ethers, methoxypolyoxyethylene alkylethers, polyoxyethylene alkylphenyl ethers, polyethylene glycol fattyacid esters, polyoxyethylene alkylamines, polyoxyethylene alkylthioethers, polyoxyethylene polyoxypropylene copolymers, polyoxyethyleneglycerol fatty acid esters, pentaerythritol fatty acid esters, propyleneglycol monofatty acid esters, polyoxyethylene propylene glycol monofattyacid esters, polyoxyethylene sorbitol fatty acid esters, fatty acidalkylolamides, and alkylamine oxides; bile acid and salts thereof (e.g.chenodeoxycholic acid, cholic acid, deoxycholic acid, dehydrocholic acidand salts thereof, and glycine or taurine conjugate thereof); ionicsurface active agents, such as sodium laurylsulfate, fatty acid soaps,alkylsulfonates, alkylphosphates, ether phosphates, fatty acid salts ofbasic amino acids; triethanolamine soap, and alkyl quaternary ammoniumsalts; and amphoteric surface active agents, such as betaines andaminocarboxylic acid salts.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, and/or indelayed fashion. Examples of embedding compositions include polymericsubstances and waxes.

The active compounds may also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

The active compounds may be in finely divided form, for example it maybe micronised.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as water or other solvents,solubilizing agents and emulsifiers such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide,oils (in particular, cottonseed, groundnut, corn, germ, olive, castor,and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan and mixtures thereof. Besidesinert diluents, the oral compositions may also include adjuvants such aswetting agents, emulsifying and suspending agents, sweetening, flavoringand perfuming agents. Suspensions, in addition to the active compounds,may contain suspending agents such as ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanthand mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolisable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilisers, preservatives,excipients and the like. The preferred lipids are the phospholipids andthe phosphatidyl cholines (lecithins), both natural and synthetic.Methods to form liposomes are known in the art, for example, Prescott,Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.(1976), p 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which maybe required. Ophthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Advantageously, the compounds of the invention may be orally active,have rapid onset of activity and low toxicity.

The compounds of the invention may have the advantage that they are moreefficacious, less toxic, longer acting, have a broader range ofactivity, more potent, produce fewer side effects, more easily absorbedthan, or have other useful pharmacological properties over, compoundsknown in the prior art.

Compounds of the invention may be useful in the therapy of a variety ofdiseases and conditions. In particular, compounds of the invention maybe useful in the treatment or prevention of diseases or disorders whichcan be prevented, alleviated or treated by modulation/inhibition ofN-myristoyl transferase (NMT) activity (referred to herein as NMTrelated diseases or disorders). Such NMT related diseases or disordersinclude but are not limited to hyperproliferative disorders, for examplecancer, microbial infections, neurological diseases/disorders anddiabetes and associated conditions.

As used herein, the term “cancer” refers to cells having the capacityfor autonomous growth, i.e., an abnormal state or conditioncharacterized by rapidly proliferating cell growth. The term is meant toinclude all types of cancerous growths or oncogenic processes,metastatic tissues or malignantly transformed cells, tissues, or organs,irrespective of histopathologic type or stage of invasiveness. The term“cancer” includes malignancies of the various organ systems, such asthose affecting, for example, lung, breast, thyroid, lymphoid,gastrointestinal, and genito-urinary tract, as well as adenocarcinomaswhich include malignancies such as most colon cancers, renal-cellcarcinoma, prostate cancer and/or testicular tumours, non-small cellcarcinoma of the lung, cancer of the small intestine and cancer of theesophagus. The term “carcinoma” is art recognized and refers tomalignancies of epithelial or endocrine tissues including respiratorysystem carcinomas, gastrointestinal system carcinomas, genitourinarysystem carcinomas, testicular carcinomas, breast carcinomas, prostaticcarcinomas, endocrine system carcinomas, and melanomas. Exemplarycarcinomas include those forming from tissue of the cervix, lung,prostate, breast, head and neck, colon and ovary.

The term “carcinoma” also includes carcinosarcomas, e.g., which includemalignant tumours composed of carcinomatous and sarcomatous tissues. An“adenocarcinoma” refers to a carcinoma derived from glandular tissue orin which the tumor cells form recognizable glandular structures. Theterm “sarcoma” is art recognized and refers to malignant tumors ofmesenchymal derivation. Further types of cancer include leukaemia, skin,intracranial and brain cancer.

By “microbial infection” is meant an infection caused by a bacterium,parasite, protozoa, virus or fungus including yeast. A “pathogen” isgenerally defined as any disease-causing organism.

A parasitic pathogen may be derived from a parasite selected from, butnot limited to, the group consisting of Trypanosoma spp. (e.g. T. cruzi,T. brucei, T. congolense), Leishmania spp. (e.g. L. major, L. donovani,L. braziliensis), Giardia spp., Trichomonas spp. (e.g. Tr. vaginalis),Entamoeba spp. (e.g. E. histolytica), Naegleria spp., Acanthamoeba spp.(e.g. A. castelleni), Schistosoma spp. (e.g. S. mansoni, S. japonicam),Plasmodium spp. (e.g. P. falciparum), Crytosporidium spp., Isosporaspp., Balantidium spp., Loa Loa, Ascaris lumbricoides, Dirofilariaimmitis, Toxoplasma ssp. (e.g To. gondii), Onchocerca spp. (e.g. O.volualno).

A viral pathogen may be derived from a virus selected from, but notlimited to, the group consisting of: Human Immunodeficiency Virus (HIV1& 2); Human T Cell Leukaemia Virus (HTLV 1 & 2); Ebola virus; humanpapilloma virus (e.g. HPV-2, HPV-5, HPV-8 HPV-16, HPV-18, HPV-31,HPV-33, HPV-52, HPV-54 and HPV-56); papovavirus; rhinovirus; poliovirus;herpesvirus; adenovirus; Epstein Barr virus; influenza virus, hepatitisB and C viruses, Variola virus, rotavirus or SARS coronavirus.

A fungal pathogen may be derived from a fungus (including yeast)selected from, but not limited to, the genera Candida spp., (e.g. C.albicans, C. tropicalis), Aspergillus spp. (e.g. A. fumigatus),Cryptococcus spp. (e.g. Cryptococcus neoformans), and Saccharomyces spp.(e.g. Saccharomyces cerevisiae), Pneumocystis spp. (e.g. Pneumocystiscarinii).

As used herein the “neurological diseases/disorder” may includeneuropsychiatric disorders, including Parkinson's Disease, AttentionDeficit Hyperactivity Disorder (ADHD), depression (bipolar disorder) andschizophrenia and addiction; neurodegenerative disorders (e.g.Alzheimer's disease, Tourette Syndrome, Parkinson's disease,Huntington's disease, Amyotrophic Lateral Sclerosis, senile chorea,Sydenham's chorea, autism, head and spinal cord trauma, acute andchromic pain, epilepsy and seizures, dementia, distonia, tremor, autism,cerebral ischemia and neuronal cell death) and disorders linked toapoptosis (particularly neuronal apoptosis).

Thus the invention provides the use of a compound of the invention, orpharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment or prevention of a NMT related disease ordisorder.

In a preferred use according to the invention the NMT related disease ordisorder is cancer. The compounds of the invention may be useful in thetherapy of a variety of cancer including, but not limited to, prostate,breast, brain (e.g. glioma), gallbladder, colon, ovarian and oral (e.g.squamous cell) cancer or leukaemia.

In a further preferred use according to the invention the NMT relateddisease or disorder is a microbial infection for example a parasite,viral or fungal infection. By way of example the parasite infection maybe caused by Trypanosoma spp. (e.g. Trypanosoma cruzi, Trypansosomabrucei) or Leishmania spp. (e.g. L. major, L. donovani) or Plasmodiumspp. (e.g. P. falciparum). The viral infection may be caused by HIV e.g.HIV1 or HIV2 or hepatitis B. The fungal infection may be caused by afungus selected from the group consisting of Candida albicans,Aspergillus Fumigatus, Pnemocystis carinii and Cryptococcus neoformans.The microbial infection may include Leishmaniasis, Trypanosomiasis,Malaria, (Invasive) Aspergillosis, Candidiasis, Pneumocystis pneumoniaand Cryptococcosis.

In a further use according to the invention the NMT related disease ordisorder is a neurological disease or disorder for example epilepsy orAlzheimer's disease.

In a yet further use according to the invention the NMT related diseaseor disorder is diabetes, ischemia or osteoporosis.

The invention further provides a method of treating a NMT relateddisease or disorder in a subject which method comprises administering tosaid subject a therapeutically effective amount of a compound, orpharmaceutically acceptable salt thereof, or composition of theinvention. Preferably the subject is a mammal for example a human.

The compounds of the invention, or pharmaceutically acceptable saltsthereof, may be administered in combination with a chemotherapeuticagent. Thus in a further aspect the invention provides a method ofincreasing the efficacy of a chemotherapeutic agent in a mammal havingcancer, said method comprising administering to said mammal an effectiveamount of a compound of the invention or pharmaceutically acceptablesalt thereof.

In a further aspect the invention provides a method of inhibiting theactivity of one or more NMT (NMT1 and NMT2), said method comprisingcontacting one or more NMT with an effective amount of the compound ofthe invention. The method may be an in vitro method. Alternatively themethod may be an in vivo method.

As used herein, “treatment” refers to clinical intervention in anattempt to alter the natural course of the individual or cell beingtreated, and may be performed either for prophylaxis or during thecourse of clinical pathology. Desirable effects include preventingoccurrence or recurrence of disease, alleviation of symptoms,diminishment of any direct or indirect pathological consequences of thedisease, lowering the rate of disease progression, amelioration orpalliation of the disease state, and remission or improved prognosis.The term, “treatment” as used herein is intended to include thetreatment and prevention of the indicated conditions/disorders

There is further provided a package or kit of parts comprising:

(1) a compound, or pharmaceutically acceptable salt thereof, asdescribed herein; together with(2) instructions to use said compound or salt in a method describedherein.

The package defined herein may comprise more than one dosage unit, inorder to provide for repeat dosing. If more than one dosage unit ispresent, such units may be the same, or may be different in terms of thedose of active agent composition and/or physical form.

Throughout the description and claims of this specification, the words“comprise” and “contain” and variations of the words, for example“comprising” and “comprises”, means “including but not limited to”, andis not intended to (and does not) exclude other moieties, additives,components, integers or steps.

Throughout the description and claims of this specification, thesingular encompasses the plural unless the context otherwise requires.In particular, where the indefinite article is used, the specificationis to be understood as contemplating plurality as well as singularity,unless the context requires otherwise.

Features, integers, characteristics, compounds, chemical moieties orgroups described in conjunction with a particular aspect, embodiment orexample of the invention are to be understood to be applicable to anyother aspect, embodiment or example described herein unless incompatibletherewith.

EXAMPLE 1 Materials and Methods

The following abbreviations are used:

Pd(dppf)Cl₂.DCM—[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex; THF—tetrahydrofuran,EtOAc—ethyl acetate; DMF—N,N-dimethylformamide;MeOH—methanol; Boc—t-butoxycarbonyl;EtOH—ethanol; CHCl₃—chloroform;DCM—dichloromethane; AcOH—acetic acid;DIPEA—diisopropylethylamine; EtOH—ethanol;Pyr—pyridine; Ar—aryl;DMSO—dimethylsulphoxide; iPr—isopropyl;Et₂O—diethylether; Me—methyl;

All NMR's were obtained either at 500 MHz on a Bruker Avance IIspectrometer or at 300 MHz on a Bruker DPX 300 spectrometer.

All LCMS's were obtained using a Bruker Daltonics mass spectrometer incombination with an Agilent 1100 series high pressure liquidchromatograph.

All Intermediates and Examples were named with the aid of BeilsteinAutonom or were given names that seemed consistent with IUPACconvention.

General Methods of Synthesis of Compounds

The following is a description of a process for preparing a compound ofthe invention or a pharmaceutically acceptable salt thereof:

a) reacting a sulfonyl compound of formula (X) with an intermediatecompound of formula (XI) in which X′ represents a leaving group forexample halo, e.g. chloro, in the presence or absence of a diluent forexample an organic solvent e.g. dichloromethane or chloroform andoptionally in the presence of a base, for example an organic amine e.g.DIPEA, triethylamine etc. but preferentially pyridine, at a temperaturein the range of 0-150° C.

Where they are not commercially available, the starting materials offormula (XI), being derived from amine-bearing heterocycles such aspyridine, isoxazole and pyrazole, may be prepared by methods analogousto those described in the accompanying examples or by standard methodswell known in the art (Labeeuw, O. et al. Tett. Asymm., 2004, 15,1899-1908 and Blay, G. et al. Tetrahedron, 2006, 62, 8069-8076).

b) reacting an intermediate sulphonamide compound of formula (XII) withan appropriately substituted aryl or heteroaryl boronic acid or asuitably reactive analogue therein, such as an aryl or heteroarylpinacolboronic ester, in the presence of a metal catalyst. e.g. Pd orderivatives thereof, such as Pd(dppf)Cl₂.DCM or Pd(PPh₃)₄, and in asolvent such as DMF or THF, optionally with water as a co-solvent, andan organic or inorganic base such as triethylamine or potassiumphosphate, and in the temperature range 0-170° C., to provide a compoundof formula (XIII).

Where the appropriate boronic acids or boronic esters are notcommercially available, compounds of formula (XIII) may be prepared byreacting an appropriately substituted aryl or heteroaryl halide withintermediate (XIV), where B(OR)₂ is typically —B(OH)₂ or any suitablyreactive ester derivative thereof, which itself can be prepared fromintermediate (XII) by an appropriate boronation reaction with aboronating reagent e.g. bispinacolatodiboron or pinacolborane, accordingto the method of Murata et al. (Murata, M; Oyama, T.; Watanabe, S;Masuda, Y., J. Org. Chem. 2000, 65, 164-168).

c) reacting an intermediate compound of formula (XII) with anappropriately substituted alkyne of formula (XV) in the presence of acopper(I) halide e.g. copper(I) iodide, a metal catalyst e.g. Pd orderivatives thereof, such as Pd(PPh3)₂Cl₂ or Pd(PPh₃)₄, and in a solventsuch as DMF or THF, with an organic or inorganic base such astriethylamine, diisopropylamine or sodium acetate, and in thetemperature range 0-170° C.

d) reacting an intermediate compound of formula (XII) with anappropriately substituted alkene in the presence of9-borabicyclo[3.3.1]nonane and a metal catalyst e.g.tetrakis-triphenylphosphine palladium (0) or Pd(dppf)Cl₂.DCM and in asolvent such as DMF or THF, with an organic or inorganic base such astriethylamine, diisopropylamine or potassium phosphate, and in thetemperature range 0-170° C., according to the methods described bySuzuki et al. (Miyaura, M.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.;Satoh, M.; Suzuki, A., J. Am. Chem. Soc., 1989, 111, 314-321) and Lynchet al. (Lynch, C. L. Bioorg. Med. Chem. Letts., 2003, 13, 119-123).

It will be understood that certain compounds of the invention initiallyobtained from any of the above processes may, where appropriate, beelaborated into certain other compounds of the invention by techniquesknown to those skilled in the art. By way of example, the conversion ofa compound of formula (XVI) to a compound of formula (XVII), where n′=1or 2, can be effected by the use of a reducing agent, for example,hydrogen gas, in combination with a heterogeneous or homogeneoustransition metal catalyst, such as Pd on charcoal, or Wilkinson'scatalyst. Alternatively, transfer hydrogenation conditions can beemployed to effect the same transformation, e.g. using tosylhydrazone orformic acid, or the use of a dissolving metal in a protic solvent i.e.lithium in liquid ammonia.

It will be understood that the conversion of a compound of formula(XIII) to a compound of formula (XVII) can also be effected via a fivestep process which comprises (i) reaction of intermediate (XII) with asuitably protected alcohol-bearing alkyne, for exampletetrahydro-2-(2-propynyloxy)-2H-pyran; (ii) catalytic reduction of thealkyne with a suitable reducing agent; (iii) deprotection of the alcoholby treatment with HCl in a suitable protic solvent, such as methanol;(iv) conversion of the alcohol to a suitably reactive leaving group suchas halo, e.g. chloro or bromo, or sulfonyl group, e.g. p-toluenesulfonylor methanesulfonyl; and (v) displacement of the intermediate thereofobtained by an appropriately substituted amine e.g. piperazine orhomopiperazine or a suitably substituted analogue thereof, in a solventsuch as DMF or THF.

A compound of formula (XII), wherein R⁴=H, can be converted into thecorresponding compound of formula (XII), wherein R⁴=(alkyl orsubstituted alkyl or substituted alkaryl etc. . . . ) by reaction withan appropriate alkyl or alkaryl halide, such as methyl iodide or benzylbromide in the presence of a strong base, typically sodium hydride, in asolvent such as DMF. Alternatively a base such as sodium carbonate,potassium carbonate or caesium carbonate may be used, in which case thereaction may be performed in DMF at elevated temperature. A compound offormula (XII), wherein R⁴=H, can be converted into the correspondingcompound of formula (XII), wherein R⁴=CF₃CH₂— or CHF₂CH₂—, by reactionwith the appropriate fluoroalkyl trifluoromethanesulfonate in thepresence of a base, typically potassium carbonate, in a solvent such asacetonitrile. A compound of formula (XII), wherein R⁴=H, can beconverted into the corresponding compound of formula (XII), whereinR⁴=CHF₂ by reaction with sodium chlorodifluoroacetate and potassiumcarbonate in acetonitrile.

A compound of formula (XIII), wherein (R⁶)_(u) represents a—(CH₂)_(n)-formyl group in the ortho-, meta-, or para-position and n=0,1 or 2, may be converted to the corresponding compound wherein (R⁶)_(u)represents a —(CH₂)_(n)—NRR′ moiety in the ortho-, meta-, orpara-position and n=0, 1 or 2, wherein NRR′ represents a substitutedamine moiety such as dimethylamino-, diethylamino-, pyrolidine-1-yl-,piperazine-1-yl-, 4-methylpiperazine-1-yl- or related substitutedanalogues of piperazine, by reaction with an appropriate amine offormula HNRR′ e.g. N-methylpiperazine in the presence of a reducingagent such as sodium cyanoborohydride or sodium triacetoxyborohydride.

A compound of formula (XIII) wherein (R⁶)_(u) represents a—(CH₂)_(n)-alcohol group in the ortho-, meta-, or para-position and n=0,1 or 2 may be converted to the corresponding compound wherein (R⁶)_(u)represents a —(CH₂)_(n)—R in the ortho-, meta-, or para-position and n=1or 2, where R is imidaz-1-yl or analogue thereof, e.g.2-methyl-imidazol-1-yl, via a two step process which comprises; (i)conversion of the alcohol to a suitable leaving group, such as halo e.g.chloro, or sulfonyl e.g. methanesulfonyl or para-toluenesulfonyl; (ii)displacement of the intermediate thereof obtained by an appropriatelysubstituted imidazole e.g. 2-methylimidazole or a suitably substitutedanalogue thereof, in a solvent such as DMF or THF, with a base such aspotassium carbonate.

A compound of formula (XIII) wherein (R⁶)_(u) represents a hydroxylgroup in the ortho-, meta-, or para-position may be converted to thecorresponding compound wherein (R⁶)_(u) represents an imidazole orsubstituted imidazole, e.g. 1H-imidazol-2-yl, 1H-imidazol-4-yl,1-methyl-imidazol-2-yl, 1-methyl-imidazol-4-yl and1-methyl-imidazol-5-yl via a two step process which comprises; (i)conversion of the phenol to a trifluoromethanesulfonate by reaction withtrifluoromethanesulphonic acid anhydride and triethylamine, in DCM at 0degC, followed by (ii) Suzuki reaction of the intermediate thereofobtained with an appropriately substituted bromo- or iodo-imidazole e.g.1-methyl-2-bromoimidazole under conditions previously described herein.

A compound of formula (XVIII) may be converted to a compound of formula(XIX), by treatment with a primary or secondary cyclic or acyclic aminein a solvent such as ethanol at elevated temperature, such as 150° C.Alternatively the transformation can be effected by reaction of an aminein the presence of a transition metal catalyst, e.g. palladium, and astrong base according to the methods described by Buchwald et al. (Wolf,J. P.; Buchwald, S. L. i J. Org. Chem., 2000, 65, 1158).

-   -   Likewise, a compound of formula (XX) may be converted to a        compound of the invention, under analogous conditions.

-   -   A compound of formula (XXI), wherein RX′ represents a suitable        leaving group, such as chloro or bromo or methanesulphonyl or        para-toluenesulphonyl, may be converted to a compound of formula        (XXI), wherein RX′ represents —NRaRb, by treatment with an amine        of formula HNRaRb under conditions which employ a solvent e.g.        DMF, DMSO or ethanol, and an inorganic or organic base e.g.        NEt₃, DIPEA, potassium carbonate or sodium carbonate, as        examples, at a temperature in the range of 0 to 170° C.    -   Similarly, a compound of formula (XXI), wherein RX′ represents a        suitable leaving group, such as chloro or bromo or        methanesulphonyl or para-toluenesulphonyl, may be converted to a        compound of formula (XXI), wherein RX′ represents —SRa, by        treatment with a thiol-bearing compound of formula HSRa under        analogous conditions as described.    -   Similarly, a compound of formula (XXI), wherein RX′ represents a        suitable leaving group, such as chloro or bromo or        methanesulphonyl or para-toluenesulphonyl, may be converted to a        compound of formula (XXI), wherein RX′ represents —ORa, by        treatment with an alcohol-bearing compound of formula HORa under        analogous conditions as described. Similarly, a compound of        formula (XXI), wherein RX′ represents a suitable leaving group,        such as chloro or bromo or methanesulphonyl or        para-toluenesulphonyl, may be converted to a compound of formula        (XXI), wherein RX′ represents —C′HRaRb, by treatment with a        compound of formula H₂C′RaRb, where Ra and/or Rb are functional        groups capable of rendering the compound represented by H₂C′RaRb        as a carbon-based nucleophile following deprotonation under        basic conditions. Such compounds represented by H₂C′RaRb        include, but are not limited to, dialkylmalonate and        thiazolidine-1,3-dione, for example.

The compounds in accordance with this invention potently inhibit theactivity of human, fungal and parasite NMT-1 and/or NMT-2.

Enzyme Inhibition Assay

Measurement of the ability of compounds to inhibit the NMT-1 and/orNMT-2 enzyme isoforms of human, trypanosome (T. brucei), leishmanial (L.major) and fungal (A. fumigatus) species was performed using amodification of the scintillation proximity assay platform describedpreviously by Georgopapadakou, N. H. et al. (22^(nd) InternationalCongress on Chemotherapy, 2001, Abstract P16.001), as follows;

N-myristoyl transferase is an enzyme that catalyses the addition ofmyristic acid from myristoyl coenzyme A to the N-terminal glycineresidue of numerous substrate proteins and peptides with the subsequentrelease of coenzyme A. ³H-labelled myristoyl coenzyme A (GE Healthcare)can be used in the reaction to transfer ³H-myristic acid to abiotinylated substrate peptide (GCGGSKVKPQPPQAK(Biotin)-Amide,Pepceuticals Inc). The reaction can be measured by the subsequentbinding of the labelled peptide to streptavidin-coated scintillationproximity assay (SPA) beads (GE Healthcare) and monitoring of β-particleexcitation of the embedded scintillant.

Compounds were solubilised in DMSO at a top concentration of 10 mM andserially diluted in half log steps to achieve a range of final assayconcentrations of 100 μM to 1 nM. Compound at each concentration(100-fold final) was added to white 384 well plates in a volume of 0.5ml. Human, A. fumigatus, T. brucei or L. major N-myristoyl transferaseenzyme, dissolved to a working concentration of 10 nM in assay buffer(30 mM Tris/HCl pH 7.4, 0.5 mM EGTA, 0.5 mM EDTA, 1.25 mM DTT, 0.1%Triton X-100), was then added to columns 1 to 11 and 13 to 23 of theplates in a volume of 20 ml. To columns 12 and 24, 20 ml assay bufferwas added to provide a no enzyme control. Following a 5 minuteincubation at room temperature the substrates(GCGGSKVKPQPPQAK(Biotin)-Amide and myristoyl coenzyme A), dissolved inassay buffer, were added to all wells in a volume of 20 ml to start thereaction. The final concentrations of peptide and ³H-myristoyl coenzymeA were 0.5 mM and 125 nM respectively and the specific activity of theradiolabel was 8 Ci/mmol. Plates were then incubated at room temperaturefor up to 50 minutes (dependant upon the period of linearity for thedifferent enzyme species) before SPA beads, suspended to 1 mg/ml in astop solution (200 mM Phosphoric Acid/NaOH pH 4, 750 mM MgCl₂), wereadded in a volume of 40 ml. Plates were then read on a TopCountmicroplate luminometer and data analysed by calculating the percentageinhibition compared to the maximum and minimum assay controls.Concentration effect curves were fitted using non linear regressionusing XLFit 4.2 and IC₅₀ values determined.

In-Vitro Antitrypanosomal Efficacy Assay

Measurement of the ability of the compounds to inhibit Trypanosome (T.brucei brucei) and Human (MRCS, human lung fibroblast cells) cell growthwas performed using a modification of the cell viability assaypreviously described by Raz, B. et al. (Acta. Trop. 68:139-14, 1997);

Compounds were solubilised in DMSO at a top concentration of 10 mM andserially diluted in half log steps to achieve a range of final assayconcentrations of 50 μM to 0.5 nM. Compound at each concentration(200-fold final) was added to clear 96 well tissue culture plates in avolume of 1 μl. 2000 cells per well in relevant growth media (HMI-9 forT. brucei as described by Hurumi, H. et al. J. Parasitol. 75(6):985-989,1989; MEM with 10% FBS for MRCS) were then added to columns 1 to 11 ofthe plates in a volume of 1994 To column 12, 200 μl media was added toprovide a no cells control. Plates were then incubated at 37° C. in anatmosphere of 5% CO₂ for 69 hours, before the addition of 20 μl of 500μM rezasurin solution, and a further incubation period of 4 hours.Plates were then read on a BioTek flx800 fluorescent plate reader andpercentage inhibition compared to the maximum and minimum assaycontrols. Concentration effect curves were fitted using non-linearregression using XLFit 4.2 and EC₅₀ values determined.

In-Vitro Antiproliferative Assay

The ability of test compounds to inhibit the proliferation of a panel ofhuman cancer cell lines was determined using the following protocol; i)cells were seeded in 96-well plates at a cell density of 3000/well, andallowed to adhere overnight prior to addition of compound or vehiclecontrol. ii) Test compounds were prepared from 10 mM DMSO stocks to givea final concentration range of 100 μM, 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM,0.1 μM, 0.03 μM and 0.01 μM, with DMSO content constant at 1%. iii) Testcompounds were incubated with the cells for 72 h at 37° C., 5% CO₂ in ahumidified atmosphere. iv) Alamar blue 10% (v/v) was then added andincubated for a further 6 h, and fluorescent product detected using theBMG FLUOstar plate reader. v) Paclitaxel was used as a standard controlinhibitor. vi) Data was analysed using a 4-parameter logistic equationin GraphPad Prism.

The following Intermediates and Examples illustrate the preparation andproperties of compounds according to the invention with reference to thefollowing FIGURE:

FIG. 1 shows a Kaplan Meier survival plot for DDD85646 in an acute modelof trypanosomiasis infection

INTERMEDIATE 14-Bromo-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prototypical Procedure for Preparation of a Sulphonamide from an Amineand a Sulfonyl Chloride;

4-Bromobenzene sulfonyl chloride (5.0 g, 19.6 mmol) was addedportionwise to a stirred solution of 4-amino-1,3,5-trimethyl-1H-pyrazole(2.45 g, 19.6 mmol) in pyridine (50 ml) at rt. The reaction was stirredfor 24 h then concentrated to dryness in vacuo. The resulting residuewas diluted with DCM (100 ml), washed with aqueous sodium hydroxidesolution (0.5M, 100 ml), organic phase separated, dried (MgSO₄),filtered and concentrated to dryness in vacuo. Trituration from Et₂O andcollection by vacuum filtration gave the title compound as a fineoff-white solid (5.1 g, 14.8 mmol, 79%). δH (D-6 DMSO, 300K). m/z (ES⁺,70V) 344.1 (MH⁺)

INTERMEDIATE 2 (DDD73234)4-Bromo-2,6-dichloro-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (5.0 g, 15.4mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (1.93 g, 15.4 mmol) inpyridine (35 ml) according to the method of intermediate 1, to give thetitle compound as an orange solid (5.64 g, 13.7 mmol, 89%). δH (D-6DMSO, 300K) 9.75 (1H, s), 8.00 (2H, s), 3.57 (3H, s), 1.93 (3H, s), 1.72(3H, s). m/z (ES⁺, 70V) 413.9 (MH⁺).

INTERMEDIATE 3 (DDD86208)4-Bromo-2-chloro-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from 4-bromo-6-chlorobenzene sulfonyl chloride (5.0 g, 17.3mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (2.16 g, 17.3 mmol) inpyridine (35 ml) according to the method of intermediate 1, to give thetitle compound as an off-white solid (4.1 g, 10.8 mmol, 62%). δH (D-6DMSO, 300K) 9.52 (1H, s), 8.05 (1H, d J 1.6 Hz), 7.72-7.63 (3H, m), 3.54(3H, s), 1.89 (3H, s), 1.69 (3H, s). m/z (ES⁺, 70V) 379.9 (MH⁺).

INTERMEDIATE 4 (DDD88004)4-Bromo-3,6-difluoro-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from 2,5-difluoro-4-bromobenzenesulfonyl chloride (2 g, 6.9mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (858 mg, 6.9 mmol) inpyridine (30 ml) according to the method of intermediate 1, to give thetitle compound as a pale yellow solid (1.9 g, 5.0 mmol, 73%). δH (D-6DMSO, 300K) 9.77 (1H, s), 8.12 (1H, dd, J 5.5 Hz 9.0 Hz), 7.55 (1H, dd J6. Hz 7.5 Hz), 3.58 (3H, s), 1.92 (3H, s), 1.74 (3H, s). m/z (ES⁺, 70V)380.0 (MH⁺).

INTERMEDIATE 5 (DDD73235) 6-Chloro-pyridine-3-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from 6-chloropyridine-3-sulfonyl chloride (4.8 g, 22.7 mmol)and 4-amino-1,3,5-trimethyl-1H-pyrazole (2.84 g, 22.7 mmol) in pyridine(35 ml) according to the method of intermediate 1, to give the titlecompound as a white solid (5.13 g, 17.1 mmol, 75%). δH (D-6 DMSO, 300K)9.51 (1H, s), 8.59 (1H, d J 2.3 Hz), 8.03 (1H, dd J 7.6 Hz 2.3 Hz), 7.77(1H, d J 7.6 Hz), 3.58 (3H, s), 1.84 (3H, s), 1.63 (3H, s). m/z (ES⁺,70V) 301.1 (MH⁺).

INTERMEDIATE 6 4-Bromo-N-(3,5-dimethyl-isoxazol-4-yl)-benzenesulfonamide

Prepared from 4-bromobenzenesulfonyl chloride (4.56 g, 17.9 mmol) and4-amino-3,5-dimethylisoxazole (2.02 g, 18.0 mmol) in pyridine (36 ml)according to the method of intermediate 1, to give the title compound asa white solid (5.15 g, 15.5 mmol, 87%). δH (CDCl₃, 300K) 7.69 (2H, dd, J6.9 Hz 1.7 Hz), 7.65 (2H, dd, J 6.9 Hz 1.7 Hz), 6.11 (1H, s), 2.12 (3H,s), 1.91 (3H, s). m/z (ES⁺, 70V) 333.0 (MH⁺).

INTERMEDIATE 74-Bromo-2,6-dichloro-N-(3,5-dimethyl-isoxazol-4-yl)-benzenesulfonamide

Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (1.00 g, 3.19mmol) and 4-amino-3,5-dimethylisoxazole (0.346 g, 3.1 mmol) in pyridine(6 ml) according to the method of intermediate 1, to give the titlecompound as a tan solid (606 mg, 1.51 mmol, 49%). δH (CDCl₃, 300K) 7.70(2H, s), 6.66 (1H, s), 2.23 (3H, s), 2.05 (3H, s). m/z (ES⁺, 70V) 400.9(MH⁺).

INTERMEDIATE 8 4-Bromo-N-(2-methyl-pyridin-3-yl)-benzenesulfonamide

Prepared from 4-bromobenzenesulfonyl chloride (4.73 g, 18.5 mmol) and2-methyl-3-aminopyridine (2.04 g, 18.9 mmol) in pyridine (36 ml)according to the method of intermediate 1, to give the title compound asa white solid (3.81 g, 11.6 mmol, 63%). δH (CDCl₃, 300K) 8.36 (1H, dd J4.8 Hz 1.5 Hz), 7.70 (1H, dd J 8.1 Hz 1.5 Hz), 7.63 (2H, dd J 6.6 Hz 2.3Hz), 7.60 (2H, dd J 6.6 Hz 2.3 Hz), 7.17 (1H, dd J 8.1 Hz 4.8 Hz), 6.89(1H, s), 2.25 (3H, s). m/z (ES⁺, 70V) 329.0 (MH⁺).

INTERMEDIATE 94-Bromo-2,6-dichloro-N-(2-methyl-pyridin-3-yl)-benzenesulfonamide

Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (1.00 g, 3.1mmol) and 2-methyl-3-aminopyridine (0.33 g, 3.1 mmol) in pyridine (6 ml)according to the method of intermediate 1, to give the title compound asa yellow solid (0.80 g, 2.0 mmol, 65%). δH (CDCl₃, 300K) 8.31 (1H, dd J4.8 Hz 1.4 Hz), 7.65 (1H, d J 1.4 Hz), 7.64 (2H, s), 7.10 (2H, m), 2.52(3H, s). m/z (ES⁺, 70V) 396.9 (MH⁺).

INTERMEDIATE 104-Bromo-2-fluoro-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from 4-bromo-2-fluorobenzenesulfonyl chloride (0.75 g, 2.7mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (0.35 g, 2.8 mmol) inpyridine (4.5 ml) according to the method of intermediate 1, to give thetitle compound as an orange solid (0.59 g, 1.6 mmol, 60%). δH (D-6 DMSO,300K) 9.60 (1H, s), 7.90 (1H, d J 9.4 Hz), 7.56 (1H, d J 8.2 Hz), 7.51(1H, d J 7.7 Hz), 3.56 (3H, s), 1.89 (3H, s), 1.69 (3H, s). m/z (ES⁺,70V) 364.0 (MH⁺).

INTERMEDIATE 114-(2-Chloro-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prototypical Procedure for Suzuki Coupling of a Boronic Ester or BoronicAcid with an Aryl Halide;

METHOD 1: A solution of the compound of intermediate 1 (1.5 g, 4.36mmol), 2-chloropyridine-4-boronic acid (684 mg, 4.35 mmol), tribasicpotassium phosphate (924 mg, 4.35 mmol) and Pd(dppf)Cl₂.DCM (100 mg,0.12 mmol) and water (1.5 ml) in oxygen-free DMF (8 ml) was heated in amicrowave at 130° C. for 1 h. The reaction was concentrated to drynessin vacuo, diluted with DCM (100 ml), washed with saturated aqueoussodium hydrogencarbonate solution (2×25 ml), dried (MgSO₄) andconcentrated in vacuo to give a residual oil. Chromatography (SiO₂,EtOAc) gave the title compound as a fine white solid (1.13 g, 2.66 mmol,61%). δH (D-6 DMSO, 300K) 8.52 (1H, d J 5.2 Hz 7.88 (2H, d J 8.4 Hz),7.74 (2H, d J 8.4 Hz), 7.58 (1H, s), 7.46 (1H, dd J 1.5 Hz 5.2 Hz), 6.36(1H, s), 3.71 (3H, s), 2.12 (3H, s), 1.62 (3H, s). m/z (ES⁺, 70V) 377.1(MH⁺).

INTERMEDIATE 12 (DDD86209)2,6-Dichloro-4-(2-chloro-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 2 (250 mg, 0.6 mmol),2-chloropyridine-4-boronic acid (108 g, 0.67 mmol), tribasic potassiumphosphate (145 mg, 0.68 mmol), Pd(dppf)Cl₂.DCM (20 mg, 0.024 mmol) andwater (0.3 ml) in oxygen-free DMF (2.5 ml) at 110° C. for 1 h accordingto the method of intermediate 11, to give the title compound as a whitesolid (212 mg, 0.47 mmol, 79%). δH (CDCl₃, 300K) 8.38 (1H, dd J 0.5 Hz5.2 Hz), 7.54 (2H, s), 7.37 (1H, dd J 1.6 Hz 5.2 Hz), 6.56 (1H, s), 3.65(3H, s), 2.09 (3H, s), 1.69 (3H, s). m/z (ES⁺, 70V) 447.0 (MH⁺).

INTERMEDIATE 134-Bromomethyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

4-Bromomethylbenzene sulfonyl chloride (3.72 g, 13.8 mmol) was addedportionwise to a solution of 4-amino-1,3,5-trimethyl-1H-pyrazole (1.73g, 13.8 mmol) and pyridine (1.5 ml) in DCM (100 ml) at rt. Concentrationin vacuo gave a solid which was collected by vacuum filtration andwashed with water (2×25 ml) then Et2O (100 ml) to give the titlecompound as a white solid (2.71 g, 7.59 mmol, 55%). δH (D-6 DMSO, 300K)9.13 (1H, s), 7.64-7.55 (4H, m), 4.77 (2H, s), 3.55 (3H, s), 1.80 (3H,s), 1.54 (3H, s). m/z (ES⁺, 70V) 358.1 (MH⁺).

INTERMEDIATE 14 3′-Formyl-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the sulphonamide of intermediate 1 (1.54 g, 4.48 mmol),3-formylphenylboronic acid (1.40 g, 10.0 mmol), tribasic potassiumphosphate (1.98 g, 9.0 mmol), Pd(dppf)Cl₂.DCM (100 mg, 0.12 mmol) andwater (2 ml) in oxygen-free DMF (12 ml) at 130° C. for 1 h according tothe method of intermediate 11, to give the title compound as a whitesolid (1.61 g, 4.36 mmol, 97%). δH (D-6 DMSO, 300K) 10.13 (1H, s), 9.19(1H, s), 8.29 (1H, t J 1.6 Hz), 8.12-8.09 (1H, m), 8.0-7.96 (3H, m),7.77-7.73 (3H, m), 3.56 (3H, s), 1.84 (3H, s), 1.61 (3H, s). m/z (ES⁺,70V) 370.1 (MH⁺).

INTERMEDIATE 15 3,5-Dichloro-3′-formyl-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the sulphonamide of intermediate 2 (1.0 g, 2.43 mmol),3-formylphenylboronic acid (440 mg, 2.91 mmol), tribasic potassiumphosphate (620 mg, 2.91 mmol), Pd(dppf)Cl₂.DCM (100 mg, 0.12 mmol) andwater (0.5 ml) in oxygen-free DMF (6.0 ml) at 130° C. for 1 h accordingto the method of intermediate 11, to give the title compound as a whitesolid (870 mg, 2.0 mmol, 82%). δH (D-6 DMSO, 300K) 10.12 (1H, s), 9.68(1H, s), 8.42 (1H, s), 8.21 (1H, d J 7.9 Hz), 8.07 (2H, s), 8.01 (1H, dJ 7.5 Hz), 7.74 (1H dd J 7.5 Hz 7.9 Hz), 3.58 (3H, s), 1.50 (3H, s),1.75 (3H, s). m/z (ES⁺, 70V) 439.2 (MH⁺).

INTERMEDIATE 16 3,5-Dichloro-4′-formyl-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the sulphonamide of intermediate 2 (1.0 g, 2.43 mmol),4-formylphenylboronic acid (440 mg, 2.91 mmol), tribasic potassiumphosphate (620 mg, 2.91 mmol), Pd(dppf)Cl₂.DCM (100 mg, 0.12 mmol) andwater (0.5 ml) in oxygen-free DMF (6.0 ml) at 130° C. for 1 h accordingto the method of intermediate 11, to give the title compound as a whitesolid (791 mg, 1.83 mmol, 75%). δH (D-6 DMSO, 300K) 10.12 (1H, s), 9.68(1H, s), 8.31 (2H, d 7.1 Hz), 8.07 (2H, s), 8.01 (2H, d J 7.1 Hz), 3.58(3H, s), 1.50 (3H, s), 1.75 (3H, s). m/z (ES⁺, 70V) 439.2 (MH⁺).

INTERMEDIATE 17 2′-Formyl-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the sulphonamide of intermediate 1 (1.0 g, 2.91 mmol),2-formylphenyl boronic acid (524 mg, 3.49 mmol), tribasic potassiumphosphate (740 mg, 3.49 mmol), Pd(dppf)Cl₂.DCM (119 mg, 0.146 mmol) andwater (2.0 ml) in oxygen-free DMF (10.0 ml) at 130 degC for 1 haccording to the method of intermediate 10, to give the title compoundas a white solid (700 mg, 1.90 mmol, 65%). δH (CDCl₃, 300K) 9.93 (1H,s), 8.05 (1H, d J 7.7 Hz), 7.85 (2 h, d J 8.5 Hz), 7.68 (1H, dt J 1.5 Hz7.6 Hz), 7.58 (1H, t J 1.5 Hz), 7.50 (1H, d J 8.5 Hz), 7.39 (1H, d J 7.7Hz), 3.69 (3H, s), 2.12 (3H, s), 1.66 (3H, s). m/z (ES⁺, 70V) 370.1(M+H⁺)

INTERMEDIATE 18 (DDD87766)4-Bromo-N-methyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prototypical Procedure for N-Alkylation of a Sulphonamide with an AlkylHalide; Sodium hydride (88 mg, 95% w/w, 3.48 mmol) was added portionwiseto a solution of Intermediate 1 (1.0 g, 2.91 mmol) in DMF (10 ml) at 0°C. When effervescence had ceased, methyl iodide (217 μl, 3.48 mmol) wasadded dropwise and the reaction was allowed to warm to rt over 4 h. Thereaction was concentrated to dryness in vacuo, diluted by addition ofDCM (30 ml), washed with water (2×15 ml), dried (MgSO₄) and concentratedin vacuo. The residue was triturated from Et₂O and collected by vacuumfiltration to give the title compound as a fine off-white solid (557 mg,1.56, 54%). δH (D-6 DMSO, 300K) 9.67 (1H, s), 8.78 (1H, d J 5.7 Hz),8.51 (1H, d J 8.6 Hz), 8.09 (1H, d J 5.8 Hz), 7.86 (1H, d J 5.6 Hz),7.50 (1H, d J 5.7 Hz), 7.21 (2H, d J 8.4 Hz), 4.17 (2H, d J 8.4 Hz),4.34 (1H, s), 4.18-4.14 (1H, m), 3.21 (1H, dd J 4.9 Hz 13.9 Hz) 2.98(1H, dd J 9.3 Hz 13.9 Hz), 1.06 (3H, s), 0.99 (3H, s). m/z (ES⁺, 70V)404.1 (MH⁺).

INTERMEDIATE 19 (DDD73490)4-Bromo-2,6-dichloro-N-methyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Was prepared from the sulphonamide of intermediate 2 (5.0 g, 12.2 mmol),sodium hydride (95% w/w, 380 mg, 15.2 mmol) according to the method ofintermediate 18 to give the title compound as a brown solid (4.56 g,10.7 mmol, 88%). δH (CDCl₃, 300K) 7.60 (2H, s), 3.71 (3H, s), 3.40 (3H,s), 2.12 (3H, s), 1.84 (3H, s). m/z (ES⁺, 70V) 427.9 (MH⁺)

INTERMEDIATE 204-Bromo-2-methyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from 4-bromo-2-methylbenzenesulfonyl chloride (0.736 g, 2.7mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (0.35 g, 2.8 mmol) inpyridine (4.5 ml) according to the method of intermediate 1, to give thetitle compound as an orange solid (906 m, 2.52 mmol, 93%). δH (D-6 DMSO,300K) 9.24 (1H, s), 7.70 (1H, d, J 1.5 Hz), 7.54 (1H, dd, J 8.5 Hz 1.5Hz), 7.48 (1H, d 8.5 Hz), 3.55 (3H, s), 2.57 (3H, s), 1.82 (3H, s), 1.59(3H, s). m/z (ES⁺, 70V) 360.0 (MH⁺).

INTERMEDIATE 21 (DDD85593)4-Bromo-2,6-dichloro-N-(3-hydroxy-propyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 2 (230 mg, 0.56 mmol),3-bromopropanol (500 mg, 3.6 mmol) and caesium carbonate (325 mg, 1.0mmol) in DMF (1.5 ml) according to the method of intermediate 18, togive the title compound as a tan solid (211 mg, 0.45 mmol, 80%). δH(CDCl₃, 300K) 7.58 (2H, s), 4.17-4.11 (2H, m), 3.86-3.75 (2H, m), 3.68(3H, s), 2.09 (3H, s), 1.79 (3H, s), 1.76-1.69 (2H, m). m/z (ES⁺, 70V)472.1 (MH⁺).

INTERMEDIATE 22 3′-Formyl-biphenyl-4-sulfonic acidmethyl-(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from Intermediate 18 (285 mg, 0.8 mmol), 3-formylphenylboronicacid (143 mg, 1.0 mmol), tribasic potassium phosphate (169 mg, 0.8mmol), Pd(dppf)Cl₂.DCM (33 mg, 0.04 mmol) and water (0.5 ml) inoxygen-free DMF (2 ml) at 130° C. for 1 h, according to the method ofintermediate 11, to give the title compound as a white solid (170 mg,0.4 mmol, 56%). δH (CDCl₃, 300K) 10.12 (1H, s), 8.13 (1H, s), 7.94 (1H,d J 7.2 Hz), 7.88 (1H, d J 6.6 Hz), 7.83 (2H, d J 7.7 Hz), 7.76 (2H, d J6.7 Hz), 7.65-7.70 (1H, m), 3.70 (3H, s), 3.22 (3H, s), 2.13 (3H, s),1.59 (3H, s). m/z (ES⁺, 70V) 384.0 (MH⁺).

INTERMEDIATE 23A (DDD88198)4-Bromo-2,6-dichloro-N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (0.68 g, 2.1mmol) and 4-amino-1,5-dimethyl-3-isobutyl-1H-pyrazole (0.35 g, 2.1 mmol)in pyridine (5 ml) according to the method of intermediate 1, to givethe title compound as a white solid (120 mg, 0.26 mmol, 12%). δH (D-6DMSO, 300K) 7.65 (2H, s), 6.54 (1H, s), 3.70 (3H, s), 2.17 (3H, s), 1.96(2H, d J 7.9 Hz), 1.74 (1H, m), 0.78 (6H, d J 6.6 Hz). m/z (ES⁺, 70V)456.0 (MH⁺).

INTERMEDIATE 23B (DDD88197)4-Bromo-2,6-dichloro-N-(5-isobutyl-1,3-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (0.35 g, 1.1mmol) and 4-amino-1,3-dimethyl-5-isobutyl-1H-pyrazole (0.18 g, 1.1 mmol)in pyridine (4 ml) according to the method of intermediate 1, to givethe title compound as an orange solid (118 mg, 0.26 mmol, 24%). δH (D-6DMSO, 300K) 7.67 (2H, s), 6.69 (1H, s), 3.71 (3H, s), 2.45 (2H, d J 7.8Hz), 1.90 (1H, m), 1.84 (3H, s), 0.91 (6H, d J 6.8 Hz). m/z (ES⁺, 70V)456.0 (MH⁺).

INTERMEDIATE 24 5′-Formyl-3′-propoxy-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the sulphonamide of intermediate 1 (1.0 g, 2.91 mmol),3-formyl-5 propoxyphenyl boronic acid (726 mg, 3.49 mmol), tribasicpotassium phosphate (740 mg, 3.49 mmol), Pd(dppf)Cl₂.DCM (119 mg, 0.146mmol) and water (2.0 ml) in oxygen-free DMF (10.0 ml) at 130° C. for 1 haccording to the method of intermediate 10, to give the title compoundas a colourless solid (424 mg, 0.99 mmol, 34%). δH (CDCl₃, 300K) 10.04(1H, s), 7.82 (2H, d J 8.5 Hz), 7.67 (2H, d J 8.5 Hz), 7.67 (1H, t J 1.4Hz), 7.43 (1H, s br), 7.39 (1H, t J 2.4 Hz), 5.81 (1H, s), 4.05 (2H, t J6.6 Hz), 3.69 (3H, s), 2.10 (3H, s), 1.87 (2H, h), 1.61 (3H, s), 1.08(3H, t J 7.5 Hz). m/z (ES⁺, 70V) 428.1 (M+H⁺).

INTERMEDIATE 25 5′-Formyl-3′-isopropoxy-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the sulphonamide of intermediate 1 (1.0 g, 2.91 mmol),3-formyl-5 isopropoxyphenyl boronic acid (726 mg, 3.49 mmol), tribasicpotassium phosphate (740 mg, 3.49 mmol), Pd(dppf)Cl₂.DCM (119 mg, 0.146mmol) and water (2.0 ml) in oxygen-free DMF (10.0 ml) at 130° C. for 1 haccording to the method of intermediate 10, to give the title compoundas a white solid (469 mg, 1.10 mmol, 38%). δH (CDCl₃, 300K) 10.04 (1H,s), 7.82 (2H, d J 8.4 Hz), 7.71 (2H, d J 8.3 Hz), 7.65 (1H, s br), 7.41(1H, s br), 7.37 (1H, t J 2.1 Hz), 5.88 (1H, s), 4.71 (1H, d J 6.1 Hz),3.69 (3H, s), 2.10 (3H, s), 1.61 (3H, s), 1.40 (6H, d J 6.1 Hz). m/z(ES⁺, 70V) 428.2 (M+H⁺).

INTERMEDIATE 264-Bromo-N-(1,5-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from 4-bromobenzenesulfonyl chloride (0.396 g, 1.55 mmol) and4-amino-1,5-dimethyl-1H-pyrazole (0.172 g, 1.55 mmol) in pyridine (3 ml)according to the method of intermediate 1, to give the title compound asa yellow solid (0.362 g, 1.10 mmol, 71%). δH (D-6 DMSO, 300K) 9.43 (1H,s), 7.80 (2H, d J 8.7 Hz), 7.58 (2H, d J 8.7 Hz), 3.63 (3H, s), 1.89(3H, s). m/z (ES⁺, 70V) 332.0 (MH⁺).

INTERMEDIATE 274-Bromo-2,6-dichloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (500 mg, 1.54mmol) and 4-amino-1,5-dimethyl-1H-pyrazole (172 mg, 1.55 mmol) inpyridine (3 ml) according to the method of intermediate 1, to give thetitle compound as a cream solid (392 mg, 0.99 mmol, 64%). δH (D-6 DMSO,300K) 9.91 (1H, s), 7.97 (2H, s), 3.64 (3H, s), 2.04 (3H, s). m/z (ES⁺,70V) 399.9 (MH⁺).

INTERMEDIATE 284-Bromo-N-(1,3-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from 4-bromobenzenesulfonyl chloride (396 mg, 1.55 mmol) and4-amino-1,3-dimethyl-1H-pyrazole (228 mg, 1.55 mmol) in pyridine (3 ml)according to the method of intermediate 1, to give the title compound asa white solid (469 mg, 1.42 mmol, 92%). δH (D-6 DMSO, 300K) 9.44 (1H,s), 7.79 (2H, d J 8.7 Hz), 7.57 (2H, d J 8.7 Hz), 7.39 (1H, s), 3.65(3H, s), 1.70 (3H, s). m/z (ES⁺, 70V) 332.0 (MH⁺).

INTERMEDIATE 294-Bromo-2,6-dichloro-N-(1,3-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (500 mg, 1.54mmol) and 4-amino-1,3-dimethyl-1H-pyrazole (228 mg, 1.55 mmol) inpyridine (3 ml) according to the method of intermediate 1, to give thetitle compound as a pale pink solid (501 mg, 1.26 mmol, 82%). δH (CDCl₃,300K) 7.65 (2H, s), 7.31 (1H, s), 6.77 (1H, s), 3.78 (3H, s), 2.04 (3H,s). m/z (ES⁺, 70V) 399.9 (MH⁺).

INTERMEDIATE 30 4-Bromo-N-(1-methyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from 4-bromobenzenesulfonyl chloride (m396 g, 1.55 mmol) and4-amino-1-methyl-1H-pyrazole (206 mg, 1.54 mmol) in pyridine (3 ml)according to the method of intermediate 1, to give the title compound asa white solid (424 mg, 1.34 mmol, 87%). δH (D-6 DMSO, 300K) 9.80 (1H,s), 7.79 (2H, d J 8.7 Hz), 7.61 (2H, d J 8.7 Hz), 7.48 (1H, s), 7.05(1H, s), 3.71 (3H, s). m/z (ES⁺, 70V) 318.0 (MH⁺).

INTERMEDIATE 314-Bromo-2,6-dichloro-N-(1-methyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (500 mg, 1.54mmol) and 4-amino-1-methyl-1H-pyrazole (206 mg, 1.54 mmol) in pyridine(3 ml) according to the method of intermediate 1, to give the titlecompound as a white solid (496 mg, 1.29 mmol, 84%). δH (D-6 DMSO, 300K)7.64 (2H, s), 7.45 (1H, s), 7.18 (1H, s), 7.01 (1H, s), 3.85 (3H, s).m/z (ES⁺, 70V) 385.9 (MH⁺).

INTERMEDIATE 324-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamidePrototypical Procedure for Conversion of an Aryl Halide to an ArylBoronic Ester;

The sulphonamide of intermediate 1 (2.22 g, 7.5 mmol),bis-pinacolatodiboron (2.27 g, 8.97 mmol), potassium acetate (880 mg,15.0 mmol) and Pd(dppf)Cl₂.DCM (110 mg) in oxygen-free dioxane (10 ml)was heated to 120° C. for 1 h in a microwave. Concentration in vacuo,dilution with DCM (100 ml), washing with water (2×20 ml), drying (MgSO₄)and concentration in vacuo gave a residue which was triturated with Et₂Oand collected by vacuum filtration to give the title compound as a palered solid (1.97 g, 5.04 mmol, 67%). δH (D-6 DMSO, 300K) 9.18 (1H, s),7.86 (2H, d J 7.7 Hz), 7.68 (2H, d J 7.7 Hz), 3.59 (3H, s), 1.82 (3H,s), 1.68 (3H, s), 1.36 (12H, s). m/z (ES⁺, 70V) 392.1 (MH⁺).

INTERMEDIATE 33N-(2-Methyl-pyridin-3-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 1 (720 mg, 2.91 mmol),bis-pinacolatodiboron (880 mg, 3.49 mmol), potassium acetate (342 mg)and Pd(dppf)Cl₂.DCM (50 mg) in oxygen-free dioxane (4 ml) at 120° C. for1 h according to the method of intermediate 32, to give the titlecompound as a tan coloured solid (497 mg, 1.33 mmol, 46%). δH (D-6 DMSO,300K) 10.03 (1H, s), 8.30 (1H, d J 4.4 Hz), 7.86 (2H, d J 8.0 Hz), 7.71(2H, d J 8.0 Hz), 7.40 (1H, d J 8.0 Hz), 7.20 (1H, dd J 4.4 Hz 8.0 Hz),2.18 (3H, s), 1.35 (12H, s).

INTERMEDIATE 34N-(3,5-Dimethyl-isoxazol-4-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 6 (1.01 g, 3.06 mmol) andbis-pinacolatodiboron (851 mg, 3.35 mmol), potassium acetate (881 mg)and Pd(dppf)Cl₂.DCM (72 mg) in oxygen-free dioxane (15 ml) at 120° C.for 2 h according to the method of intermediate 32, to give the titlecompound as a tan coloured solid (661 mg, 1.75 mmol, 57%). δH (CDCl₃,300K) 7.93 (2H, d J 8.3 Hz), 7.75 (2H, d J 8.3 Hz), 5.86 (1H, s), 2.06(3H, s), 1.86 (3H, s), 1.38 (12H, s). m/z (ES⁺, 70V) 379.1 (MH⁺).

INTERMEDIATE 352,6-Dichloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 2 (1.0 g, 2.42 mmol) andbis-pinacolatodiboron (700 mg, 2.76 mmol), potassium acetate (750 mg)and Pd(dppf)Cl₂.DCM (60 mg) in oxygen-free dioxane (12 ml) at 120° C.for 2 h according to the method of intermediate 32, to give the titlecompound as an orange-brown solid (1.0 g, 2.17 mmol, 90%). δH (CDCl₃,300K) 7.83 (2H, s), 6.70 (1H, s), 3.70 (3H, s), 2.14 (3H, s), 1.79 (3H,s), 1.35 (12H, s). m/z (ES⁺, 70V) 378.0 ([M minus pinacol]H⁺).

INTERMEDIATE 364-[3-(Tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamidePrototypical Procedure for Sonogashira Coupling of an Aryl Halide to anAlkyne;

The sulphonamide of intermediate 1 (1.95 g, 6.76 mmol),tetrahydro-2-(2-propynyloxy)-2H-pyran (3.5 ml, 25.0 mmol), CuI (25 mg,0.13 mmol) and Pd(PPh₃)₄ (100 mg, 0.08 mmol), in DMF (15 ml) and NEt₃(10 ml) under argon, was heated at 110° C. for 1 h. The reaction wasconcentrated in vacuo, diluted with DCM (100 ml), washed with brine(2×25 ml), dried (MgSO4) and concentrated in vacuo to give a crude oil.Chromatography (SiO₂, EtOAc) gave the title compound as a white solid(1.95 g, 4.83 mmol, 71%). (D-6 DMSO, 300K) 9.71 (1H, s), 8.15 (2H, d J8.3 Hz), 7.91 (2H, d J 8.3 Hz), 4.88 (1H, s), 4.58 (1H, d J 16.5 Hz),4.49 (1H, d J 16.5 Hz), 3.85-3.75 (1H, m), 3.61 (3H, s), 3.57-3.51 (1H,m), 1.95 (3H, s), 1.78-1.67 (2H, m), 1.75 (3H, s), 1.61-1.45 (4H, m br).

INTERMEDIATE 374-(3-Hydroxy-propyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

The sulphonamide of intermediate 36 (2.0 g, 4.96 mmol) and palladium oncharcoal (500 mg, 10% w/w) in methanol (40 ml) under hydrogen wasstirred at rt for 24 h. The reaction was filtered through celite and theresulting clear solution was treated with 2M HCl in THF (5 ml) andstirred for a further 3 h. Concentration in vacuo and purification bychromatography (SiO₂, EtOAc: MeOH 5:1) gave the title compound as awhite powder (1.29 g, 3.99 mmol, 87%). δH (D-6 DMSO, 300K) 8.99 (1H, s),7.52 (2H, d J 8.3 Hz), 7.38 (2H, d J 8.3 Hz), 4.55 (1H, s br), 3.55 (3H,s), 3.39 (2H, t J 6.4 Hz), 2.69 (2H, m), 1.80 (3H, s), 1.72 (2H, p J 6.4Hz), 1.53 (3H, s). m/z (ES⁺, 70V) 324.1 (MH⁺).

INTERMEDIATE 382,6-Dichloro-4-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 2 (3.4 g, 8.23 mmol),tetrahydro-2-(2-propynyloxy)-2H-pyran (3.5 ml, 25.0 mmol), CuI (50 mg,0.26 mmol) and Pd(PPh₃)₄ (250 mg, 0.2 mmol), in DMF (25 ml) and NEt₃ (10ml) according to the method of intermediate 35, to give the titlecompound as a white solid (2.81 g, 5.97 mmol, 73%). δH (D-6 DMSO, 300K)9.71 (1H, s), 7.79 (2H, s), 4.88 (1H, s), 4.58 (1H, d J 16.5 Hz), 4.49(1H, d J 16.5 Hz), 3.85-3.75 (1H, m), 3.61 (3H, s), 3.57-3.51 (1H, m),1.95 (3H, s), 1.78-1.67 (2H, m), 1.75 (3H, s), 1.61-1.45 (4H, m br).

INTERMEDIATE 39 4-Piperidin-3-yl-piperazine-1-carboxylic acid tert-butylester

1-Benzyl-3-piperidone hydrochloride (700 mg, 2.7 mmol), triethylamine(270 mg, 2.7 mmol) and 1-(tert-butoxycarbonyl)-piperizine (500 mg, 2.7mmol) in DCM, was stirred at rt for 1 h, then heated to 50° C. for 40min. Sodium triacetoxyborohydride (1.12 g, 5.3 mmol) was added and thereaction mixture allowed to cool, with stirring, over 12 h thenconcentrated to dryness in vacuo. The residue was partioned betweenDCM/water, the organics dried (MgSO4) and concentrated to dryness invacuo. The resulting residue in EtOH (10 ml) was hydrogenated with 10%w/w palladium on carbon (200 mg) under hydrogen at rt for 18 h. Thereaction was filtered through celite and concentrated to dryness invacuo to give 3-piperazine-1-yl-piperidine as a pale yellow gum (700 mg,2.6 mmol, 97%). 8H (CDCl₃, 300K) 3.43-3.37 (4H, m br), 3.21 (1H, d br, J11.6 Hz), 3.01 (1H, d br, J 12.2 Hz), 2.59-2.47 (6H, m br), 2.45-2.38(1H, m), 1.99-1.92 (1H, m br), 1.82-1.75 (1H, m), 1.58-1.48 (1H, m),1.45 (9H, s), 1.42-1.33 (1H, m). m/z (ES⁺, 70V) 270.3 (MH⁺).

INTERMEDIATE 40 (DDD100805)4-bromo-2,6-dichloro-N-(difluoromethyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide

A well-stirred slurry containing the compound of intermediate 2 (3.0 g,7.2 mmol), potassium carbonate (3.0 g, 21 mmol) and sodiumchlorodifluoroacetate (3.3 g, 21 mmol) in acetonitrile (100 ml) washeated to 60° C. for 48 h. The resulting slurry was then concentrated invacuo, diluted with DCM (100 ml) and water (100 ml), the organic phaseseparated, dried (MgSO₄) and concentrated in vacuo. Trituration of theresidue with diethyl ether gave a precipitate which was collected byvacuum filtration and dried to give the title compound as a fine whitepowder (2.05 g, 4.43 mmol, 62%). δH (CDCl₃, 300K) 7.61 (2H, s), 7.34(1H, dd J 59.4 Hz 61.2 Hz), 3.67 (3H, s), 2.01 (3H, s), 1.71 (3H, s).m/z (ES⁺, 70V) 464.1 (MH⁺).

INTERMEDIATE 414-Bromo-N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from 4-bromobenzenesulfonyl chloride (8.41 g, 32.9 mmol) andthe amine of intermediate 46 (5.23 g, 31.3 mmol) in pyridine (80 ml)according to the method of intermediate 1, to give the title compound asa pale yellow solid (9.57 g, 24.8 mmol, 79%). δH (CDCl₃, 300K) 7.61 (4H,m), 5.74 (1H, bs), 3.69 (3H, s), 2.07 (3H, s), 1.78 (2H, d J 7.0 Hz),1.69 (1H, m), 0.75 (6H, d J 6.5 Hz). m/z (ES⁺, 70V) 386.1 (MH⁺).

INTERMEDIATE 424-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 41 (1.00 g, 2.59 mmol)and bis-pinacolatodiboron (780 mg, 3.07 mmol), potassium acetate (5601mg, 5.70 mmol) and Pd(dppf)Cl₂.DCM (80 mg) in oxygen-free dioxane (8 ml)at 120° C. for 40 min according to the method of intermediate 32, togive the title compound as a grey coloured solid (919 mg, 2.12 mmol,82%). δH (D-6 DMSO, 300K) 323K, 50° C. 8.97 (1H, s), 7.82 (2H, d, J 8.2Hz), 7.67 (2H, d J 8.2 Hz), 3.56 (3H, s), 1.90 (2H, d J 7.1 Hz), 1.75(3H, s), 1.72 (1H, m), 1.32 (12H, s), 0.72 (6H, d J 6.6 Hz). m/z (ES⁺,70V) 434.2 (MH⁺).

INTERMEDIATE 43 1,5-Dimethyl-3-(2-methylprop-1-enyl)-1H-pyrazole

A suspension of isopropyltriphenylphosphonium iodide (5.23 g, 12.1 mmol)in THF (35 ml) at −20° C. was treated dropwise with a 1.6 M solution ofbutyllithium in hexanes (7.5 ml, 12 mmol). The mixture was stirred at−20° C. for 45 minutes before a solution of1,5-dimethyl-1H-pyrazole-3-carboxaldehyde (1.20 g, 9.68 mmol) in THF (50ml) was added. The thick suspension was allowed to warm to roomtemperature and stirred for 24 hours. The reaction mixture was treatedwith saturated aqueous ammonium chloride (150 ml) and the phasesseparated. The aqueous phase was back-extracted with ethyl acetate (3×50ml) and the combined organic phases were dried (Na₂SO₄) andconcentrated. The residue was extracted with petroleum ether (2×100 ml)and the combined extracts were concentrated to afford a yellow oil whichwas purified by chromatography (SiO₂, 0-100% EtOAc-petroleum ether) togive the title compound as a colourless solid (1.56 g, 9.68 mmol). δH(CDCl₃, 300K) 6.15 (1H, m), 6.01 (1H, s), 3.75 (3H, s), 2.26 (3H, s),1.96 (3H, d J 0.8 Hz), 1.89 (3H, d J 1.2 Hz). m/z (ES⁺, 70V) 151.1(MH⁺).

INTERMEDIATE 44 3-Isobutyl-1,5-dimethyl-1H-pyrazole

A solution of the compound of intermediate 43 (1.56 g, 9.68 mmol) inmethanol (50 ml) was purged with argon and treated with 10% palladium oncarbon (0.291 g). The reaction vessel was purged with hydrogen andstirred at room temperature overnight. The reaction vessel was purgedwith argon and further 10% palladium on carbon (0.498 g) was added. Themixture stirred under hydrogen for a further 24 hours, then filteredthrough celite and concentrated. The residue was resuspended inpetroleum ether 40-60 (100 ml), filtered and concentrated. The resultingresidue was again suspended in petroleum ether (50 ml), re-filtered andconcentrated to give the title compound (1.064 g, 6.99 mmol, 72%) as apale yellow oil. δH (CDCl₃, 300K) 5.78 (3H, s), 3.71 (3H, s), 2.40 (2H,d J 7.1 Hz), 2.22 (31-1, s), 1.87 (1H, m), 0.92 (6H, d J 6.6 Hz). m/z(ES⁺, 70V) 153.1 (MH⁺).

INTERMEDIATE 45 3-Isobutyl-1,5-dimethyl-4-nitro-1H-pyrazole

The compound of intermediate 44 (1.049 g, 6.89 mmol) at 0° C. wastreated with concentrated sulphuric acid (3.5 ml, 66 mmol). Nitric acid(90%, 2.8 ml, 67 mmol) was added dropwise at the same temperature. Thecooling bath was removed and the mixture heated at 100° C. for 2 h. Themixture was then cooled, poured onto ice (150 ml), basified with aqueoussodium hydroxide (2M, 100 ml) and extracted with diethyl ether (3×100ml). The combined organic extracts were washed with brine, dried(Na₂SO₄) and concentrated to give the title compound as a yellow oil(1.082 g, 5.49 mmol, 80%). 8H (CDCl₃, 300K) 3.79 (3H, s), 2.77 (2H, d J7.1 Hz), 2.60 (3H, s), 2.04 (1H, m), 0.94 (6H, d J 6.7 Hz). m/z (ES⁺,70V) 198.1 (MH⁺).

INTERMEDIATE 46 3-Isobutyl-1,5-dimethyl-1H-pyrazol-4-amine

The compound of intermediate 45 (1.072 g, 5.44 mmol) in methanol (25 ml)under argon was treated with 10% palladium on carbon (0.174 g). Thereaction vessel was purged with hydrogen and stirred at room temperaturefor 23 hours. The reaction mixture was filtered through a plug of celiteand concentrated. The residue was dissolved in dichloromethane,re-filtered and concentrated to give the title compound as a red oil(0.886 g, 5.30 mmol, 97%). δH (CDCl₃, 300K) 3.67 (3H, s), 2.48 (2H,br.s), 2.39 (2H, d J 7.2 Hz), 2.13 (3H, s), 1.92 (1H, m), 0.94 (6H, d J6.7 Hz). m/z (ES⁺, 70V) 168.2 (MH⁺).

INTERMEDIATE 474-bromo-2,6-dichloro-N-(2,2,2-trifluoroethyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide

The compound of intermediate 2 (200 mg, 0.48 mmol) and K₂CO₃ (127 mg,0.96 mmol) in acetonitrile (2.0 mL) was, treated dropwise with2,2,2-trifluoroethyl methanesulphonate (0.139 mL, 223 mg, 0.139 mmol)and the mixture heated in a microwave at 100° C. for 30 min. The mixturewas then diluted with ethyl acetate (30.0 mL) and the organic layerwashed with water (2×10 mL), brine (10 mL), dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by columnchromatography (SiO₂, 6:4 Hexanes:EtOAc) to give the title compound as acolourless solid (217 mg, 0.44 mmol, 91%). δH (CDCl₃, 300K) 7.58 (2H,s), 4.82-4.68 (1H, m), 3.97-3.68 (1H, m), 3.68 (3H, s), 2.17 (3H, s),1.68 (3H, s). m/z (ES⁺, 70V) 496.2 (M+H⁺).

EXAMPLE DDD734986-(8-Amino-3,4-dihydro-1H-isoquinolin-2-yl)-pyridine-3-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the sulphonamide of intermediate 5 (1.33 gmg, 4.43 mmol)and 5-amino-1,2,3,4-tetrahydroisoquinoline (1.31 g, 8.8 mmol) in ethanol(0.75 ml), according to the method of example DDD86213, to give thetitle compound as a white powder (1.21 g, 2.94 mmol, 66%). δH (CDCl₃,300K) 8.41 (1H, d J 2.5 Hz), 7.64 (1H, dd J 2.5 Hz 9.1 Hz), 7.36 (1H,s), 7.03 (1H, t J 7.8 Hz), 6.69 (2H, t J 7.8 Hz), 6.58 (1H, d J 9.1 Hz),4.70 (2H, s), 3.95 (2H, t J 6.0 Hz), 3.62 (3H, s), 2.72 (2H, t J 6.0Hz), 2.01 (3H, s), 1.74 (3H, s). m/z (ES⁺, 70V) 413.2 (MH⁺).

EXAMPLE DDD856026-[2-(4-Methyl-piperazin-1-yl)-ethylamino]-pyridine-3-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the sulphonamide of intermediate 5 (225 mg, 0.75 mmol) and4-(2-aminoethyl)-methylpiperazine (0.5 ml) in ethanol (0.75 ml),according to the method of example DDD86213, to give the title compoundas a white powder (198 mg, 0.49 mmol, 65%). δH (D-6 DMSO, 300K) 8.77(1H, s), 8.07 (1H, d J 2.4 Hz), 7.45 (1H, dd J 2.2 Hz 8.9 Hz), 7.28 (1H,s br), 6.54 (1H, d J 8.9 Hz), 3.57 (3H, s), 3.44-3.39 (2H, m), 2.41 (2H,t J 6.1 Hz), 2.41 (4H, s br), 2.36-2.31 (4H and 3H, s br), 2.16 (3H, s),1.89 (3H, s), 1.67 (3H, s). m/z (ES⁺, 70V) 408.2 (MH⁺).

EXAMPLE DDD856462,6-Dichloro-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 2 (250 mg, 0.61 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (211 mg, 0.73mmol), tribasic potassium phosphate (155 mg, 0.73 mmol), andPd(dppf)Cl₂.DCM (30 mg, 0.36 mmol) in DMF (2.5 ml) and water (0.50 ml),according to the method of intermediate 11, to give the title compoundas an off-white powder (150 mg, 0.30 mmol, 50%). δH (D-6 DMSO, 300K)9.79 (1H, s), 8.25 (1H, d J 5.9 Hz), 8.20 (2H, s), 7.61 (1H, s), 7.40(1H, d J 5.9 Hz), 4.08 (4H, s br), 3.63 (3H, s), 3.28 (4H, s br), 2.00(3H, s), 1.77 (3H, s). m/z (ES⁺, 70V) 496.1 (MH⁺).

EXAMPLE DDD862062-Chloro-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 3 (500 mg, 1.3 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (580 mg, 2.0mmol), tribasic potassium phosphate (427 mg, 2.0 mmol), andPd(dppf)Cl₂.DCM (50 mg, 0.06 mmol) in DMF (3.0 ml) and water (0.75 ml),according to the method of intermediate 11, to give the title compoundas an off-white powder (412 mg, 0.89 mmol, 68%). δH (D-6 DMSO, 300K)8.20 (1H, d J 5.2 Hz), 8.14 (1H, d J 1.7 Hz), 7.84 (1H, dd J 1.75 Hz 8.3Hz), 7.79 (1H, d J 8.3 Hz), 7.13 (1H, s), 6.99 (1H, dd J 1.15 Hz 5.2Hz), 3.55 (3H, s), 3.51 (4H, s br), 2.79 (4H, s br), 1.90 (3H, s), 1.69(3H, s). m/z (ES⁺, 70V) 461.2 (MH⁺).

EXAMPLE DDD862112,6-Dichloro-4-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared by heating the chloropyridine of intermediate 12 (90 mg, 0.2mmol) with N-methylpiperazine (100 μl) in EtOH (1.5 ml) at 150° C. for 1h according to the method of DDD86213 to give the title compound as anoff-white powder (45 mg, 0.08 mmol, 40%). δH (CDCl₃, 300K) 8.54 (1H, d J5.1 Hz), 7.57 (1H, d J 1.8 Hz), 7.53 (1H, d J 0.95 Hz), 7.46 (1H, s),7.42 (1H, dd J 1.6 Hz 5.1 Hz), 3.69 (3H, s), 3.29 (4H, s br), 2.66 (3H,s), 2.42 (4H, s br), 2.17 (3H, s), 1.80 (3H, s). m/z (ES⁺, 70V) 509.1(MH⁺).

EXAMPLE DDD86212 3′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-sulfonicacid (1,3,6-trimethyl-1H-pyrazol-4-yl)-amide

Prototypical Procedure for the Reductive Amination of an Aldehyde withan Alkylamine;

The aldehyde of intermediate 14 (200 mg, 0.54 mmol), N-methylpiperazine(100 mg, 1.0 mmol) and sodium triacetoxyborohydride (400 mg, 1.90 mmol)in CHCl₃ (15 ml) was heated at 50° C. for 24 h. Dilution with DCM (25ml), washing with water (2×10 ml), drying (MgSO₄) and concentration invacuo gave a gum which was subjected to chromatography (SiO₂, 50:10:1EtOAc: MeOH: saturated aqueous ammonia solution) to give the titlecompound as a white powder (217 mg, 0.48 mmol, 89%). δH (D-6 DMSO, 300K)9.20 (1H, s), 8.11 (1H, s br), 7.96 (2H, d J 8.4 Hz), 7.83 (1H, d J 6.95Hz), 7.71 (2H, d J 8.4 Hz), 7.67 (1H, s br), 7.59 (1H, t J 7.6 Hz), 3.63(2H, s), 3.57 (3H, s), 3.44 (4H, s br), 2.81 (4H, s br), 1.85 (3H, s),1.58 (3H, s). m/z (ES⁺, 70V) 453.1 (MH⁺).

EXAMPLE DDD862134-(2-Piperazin-1-yl-pyridin-4-yl)-N-(1,3,6-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prototypical Procedure for Preparation of a 2-Aminopyridine byDisplacement Reaction of a 2-Chloropyridine with an Alkylamine;

METHOD 1: The compound of intermediate 11 (250 mg, 0.66 mmol) andpiperazine (500 mg, 5.8 mmol) in EtOH (0.75 ml) was heated at 155° C.for 2 h by microwave in a sealed vessel. Dilution with DCM (25 ml),washing with aqueous sodium hydrogencarbonate solution (2×5 ml), drying(MgSO₄) and concentration in vacuo gave a residual oil which wassubjected to chromatography (SiO₂, 50:10:1 EtOAc:MeOH: saturated aqueousammonia solution) to give the title compound as a white powder (189 mg,0.44 mmol, 67%). δH (D-6 DMSO, 300K) 8.24 (1H, d J 5.2 Hz), 8.00 (2H, ddJ 1.8 Hz 6.7 Hz), 7.74 (2H, dd J 1.8 Hz 6.7 Hz), 7.12 (1H, s), 7.00 (1H,dd J 5.2 Hz 1.4 Hz), 3.60 (3H, s), 3.54 (4H, s br), 2.84 (4H, s br),1.87 (3H, s), 1.68 (3H, s). m/z (ES⁺, 70V) 426.1 (MH⁺).

METHOD 2: Alternatively this compound could be prepared by Suzukireaction of the sulphonamide of intermediate 1 (500 mg, 1.68 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (581 mg, 2.0mmol), tribasic potassium phosphate (427 mg, 2.0 mmol), andPd(dppf)Cl₂.DCM (50 mg, 0.06 mmol) in DMF (3.0 ml) and water (0.75 ml),according to the method of intermediate 11, to give the title compoundas an off-white powder (381 mg, 0.89 mmol, 53%).

EXAMPLE DDD862922,6-Dichloro-4-[2-(3-dimethylamino-pyrrolidin-1-yl)-pyridin-4-yl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared by heating the chloropyridine of intermediate 12 (250 mg, 0.58mmol) with 3-dimethylaminopiperidine (200 μl) in EtOH (1.5 ml) at 155°C. for 1 h according to the method of DDD86213 to give the titlecompound as a white powder (150 mg, 0.29 mmol, 49%). δH (CDCl3, 300K)8.48 (1H, d J 5.1 Hz), 7.49 (2H, s), 7.39 (1H, d J 4.7 Hz), 7.32 (1H,s), 3.76-3.46 (6H, s br), 3.63 (3H, s), 3.46-3.39 (1H, m), 2.75 (2H, sbr), 2.28 (2H, s br), 2.05 (3H, s), 1.85 (3H, s), 1.56 (2H, s br). m/z(ES⁺, 70V) 523.2 (MH⁺).

EXAMPLE DDD862972,6-Dichloro-4-[2-(2-methylamino-ethylamino)-pyridin-4-yl]N-(1,3,6-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared by heating the chloropyridine of intermediate 12 (250 mg, 0.58mmol) with N-methylethylenediamine (200 μl) in EtOH (1.5 ml) at 155° C.for 1 h according to the method of DDD86213 to give the title compoundas a white powder (134 mg, 0.28 mmol, 48%). δH (D-6 DMSO, 300K) 8.53(1H, d J 5.2 Hz), 7.98 (1H, d J 0.9 Hz), 7.85 (1H, dd J 1.5 Hz 5.2 Hz),7.28 (1H, s), 7.21 (1H, d J 1.5 Hz), 7.04 (1H, d J 1.5 Hz), 3.60 (3H,s), 3.24-3.20 (2H, m), 2.64-2.58 (2H, m), 2.29 (3H, s), 1.98 (3H, s),1.82 (3H, s). m/z (ES⁺, 70V) 483.1 (MH⁺).

EXAMPLE DDD863022,6-Dichloro-4-{2-[2-(pyridin-2-ylamino)-ethylamino]-pyridin-4-yl}-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared by heating the chloropyridine of intermediate 12 (250 mg, 0.58mmol) with N-(2-pyridyl)ethylenediamine (200 μl) in EtOH (1.5 ml) at155° C. for 1 h according to the method of DDD86213 to give the titlecompound as a white powder (111 mg, 0.2 mmol, 35%). δH (D-6 DMSO, 300K)9.41 (1H, s), 8.51 (1H, d J 5.1 Hz), 7.93 (1H, d J 4.9 Hz), 7.91 (1H,s), 7.79 (1H, d J 5.2 Hz), 7.36 (1H, t J 7.1 Hz), 7.27 (1H, s),7.20-7.18 (1H, m), 7.17 (1H, s), 6.60 (1H, s), 6.54-6.44 (2H, m), 3.55(3H, s), 3.41-3.23 (4H, m), 1.92 (3H, s), 1.79 (3H, s). m/z (ES⁺, 70V)546.1 (MH⁺).

EXAMPLE DDD863032,6-Dichloro-4-{2-[2-(pyridin-2-ylamino)-ethylamino]-pyridin-4-yl}-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared by heating the chloropyridine of intermediate 12 (250 mg, 0.58mmol) with ethylenediamine (200 μl) in EtOH (1.5 ml) at 155° C. for 1 haccording to the method of DDD86213 to give the title compound as awhite powder (137 mg, 0.29 mmol, 50%). δH (D-6 DMSO, 300K) 8.49 (1H, d J4.1 Hz), 7.93 (1H, s), 7.80 (1H, d J 4.9 Hz), 7.22 (1H, s br), 7.17 (1H,s), 7.01 (1H, s), 4.03 (2H, s br), 3.55 (3H, s), 3.16 (2H, s br), 2.63(2H, t J 7.1 Hz), 1.94 (3H, s), 1.78 (3H, s). m/z (ES⁺, 70V) 469.2(MH⁺).

EXAMPLE DDD863082,6-Dichloro-4-[2-(3-imidazol-1-yl-propylamino)-pyridin-4-yl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared by heating the chloropyridine of intermediate 12 (250 mg, 0.58mmol) with N-(3-aminopropyl)imidazole (200 μl) in EtOH (1.5 ml) at 155°C. for 1 h according to the method of DDD86213 to give the titlecompound as a white powder (130 mg, 0.24 mmol, 41%). δH (CDCl₃, 300K)8.46 (1H, dd J 0.5 Hz 5.1 Hz), 7.52 (1H, s), 7.46 (1H, dd J 0.5 Hz 1.5Hz), 7.35 (1H, dd J 1.5 Hz 5.2 Hz), 7.24 (1H, t J 4.9 Hz), 7.1 Hz (1H,s), 7.00 (1H, d J 1.8 Hz), 6.83 (2H, s), 6.58 (1H, d J 1.8 Hz), 3.92(2H, t J 6.1 Hz), 3.60 (3H, s), 3.04 (2H, q J 6.1 Hz), 2.13 (3H, s),2.05 (2H, p J 6.1 Hz), 1.89 (3H, s). m/z (ES⁺, 70V) 534.1 (MH⁺).

EXAMPLE DDD863092,6-Dichloro-4-[2-(2-dimethylamino-ethylamino)-pyridin-4-yl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared by heating the chloropyridine of intermediate 12 (250 mg, 0.58mmol) with N,N-dimethylethylenediamine (200 μl) in EtOH (1.5 ml) at 155°C. for 1 h according to the method of DDD86213 to give the titlecompound as a white powder (70 mg, 0.14 mmol, 24%). δH (CDCl₃, 300K)8.50 (1H, d J 5.1 Hz), 7.53 (1H, s), 7.44 (1H, d J 3.8 Hz), 7.39 (1H, tJ 4.5 Hz), 7.02 (1H, s), 6.98 (1H, s), 6.76 (1H, s), 3.68 (3H, s), 3.27(″h, s br), 2.60 (2H, s br), 2.31 (6H, s br), 2.14 (3H, s), 2.89 (3H,s). m/z (ES⁺, 70V) 497.1 (MH⁺).

EXAMPLE DDD86312 3′-Diethylaminomethyl-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the aldehyde of intermediate 14 (80 mg, 0.23 mmol),diethylamine (0.088 ml, 50 mg, 0.069 mmol) and sodiumtriacetoxyborohydride (146 mg, 0.069 mmol) in CHCl₃ (5.0 ml) at 50° C.for 24 h according to the method of example DDD86212 to give the titlecompound as a white solid (55 mg, 0.13 mmol, 56%). δH (CDCl₃, 300K) 7.78(2H, d J 8.6 Hz), 7.71 (2H, d J 8.5 Hz), 7.66 (1H, s br), 7.50 (1H, d J6.8 Hz), 7.42 (2H, d J 5.8 Hz), 5.84 (1H, s), 3.71 (1H, s br), 3.68 (3H,s), 2.64 (3H, s br), 2.08 (3H, s), 1.62 (3H, s), 1.13 (6H, s br). m/z(ES⁺, 70V) 427.2 (MH⁺).

EXAMPLE DDD86314 3′-Morpholin-4-ylmethyl-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the aldehyde intermediate 14 (150 mg, 0.41 mmol),morpholine (107 μl, 107 mg, 1.23 mmol) and sodium triacetoxyborohydride(261 mg, 1.23 mmol) in CHCl₃ (10.0 ml) at 50° C. for 24 h according tothe method of example DDD86212 to give the title compound as a whitesolid (90 mg, 0.21 mmol, 50%). δH (CDCl₃, 300K) 7.79 (2H, d J 8.3 Hz),7.69 (2H, d J 8.3 Hz), 7.57 (1H, s br), 7.50 (1H, d J 7.5 Hz), 7.43 (1H,t J 7.5 Hz), 7.39 (1H, d J 7.5 Hz), 5.74 (1H, s br), 3.73 (3H, t J 4.6Hz), 3.69 (3H, s), 3.57 (2H, s), 2.49 (3H, s br), 2.11 (3H, s), 1.61(3H, s), 1.55 (1H, s br). m/z (ES⁺, 70V) 441.1 (MH⁺).

EXAMPLE DDD863154-[4′-(1,3,5-Trimethyl-1H-pyrazol-4-ylsulfamoyl)-biphenyl-3-ylmethyl]-piperazine-1-carboxylicacid tert-butyl ester

Prepared from the aldehyde of intermediate 14 (150 mg, 0.41 mmol), N-Bocpiperazine (229 mg, 1.23 mmol) and sodium triacetoxyborohydride (261 mg,1.23 mmol) in CHCl₃ (10.0 ml) at 50° C. for 24 h according to the methodof example DDD86212 to give the title compound as a white solid (120 mg,0.14 mmol, 54%). δH (CDCl₃, 300K) 7.79 (2H, d J 8.4 Hz), 7.69 (2H, d J8.4 Hz), 7.56 (1H, s br), 7.50 (1H, d, J 7.7 Hz), 7.43 (1H, t J 7.6 Hz),7.38 (1H, d, J 7.7 Hz), 5.74 (1H, s), 3.69 (3H, s), 3.58 (2H, s), 3.45(4H, t J 5.0 Hz), 2.43 (4H, t J 4.5 Hz), 2.11 (3H, s), 1.54 (3H, s),1.46 (9H, s). m/z (ES⁺, 70V) 540.1 (MH⁺).

EXAMPLE DDD863163′-[(2-Dimethylamino-ethylamino)-methyl]biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the aldehyde of intermediate 14 (150 mg, 0.41 mmol),NN′-dimethylethylenediamine (134 μl, 108 mg, 1.23 mmol) and sodiumtriacetoxyborohydride (261 mg, 1.23 mmol) in CHCl₃ (10.0 ml) at 50° C.for 18 h according to the method of example DDD86212 to give the titlecompound as a white solid (60 mg, 0.14 mmol, 33%). δH (CDCl₃, 300K) 7.78(2H, d J 8.4 Hz), 7.69 (2H, d J 8.5 Hz), 7.59 (1H, s br), 7.48 (1H, d J7.6 Hz), 7.43 (1H, t J 7.5 Hz), 7.38 (1H, d J 7.5 Hz), 5.75 (1H, s),3.89 (2H, s), 3.68 (3H, s), 2.74 (2H, t J 5.9 Hz), 2.46 (2H, t J 6.2Hz), 2.22 (6H, s), 2.08 (3H, s), 1.63 (3H, s). m/z (ES⁺, 70V) 442.1(MH⁺).

EXAMPLE DDD86317 3′-Piperazin-1-ylmethyl-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the aldehyde of intermediate 14 (150 mg, 0.41 mmol),piperazine (106 mg, 1.23 mmol) and sodium triacetoxyborohydride (261 mg,1.23 mmol) in CHCl₃ (10.0 ml) at 50° C. for 24 h according to the methodof example DDD86212 to give the title compound as a white solid (94 mg,0.21 mmol, 52.0%). δH (CDCl₃, 300K) 7.79 (2H, d J 8.4 Hz), 7.69 (2H, d J8.3 Hz), 7.56 (1H, s br), 7.49 (1H, d J 7.6 Hz), 7.42 (1H, t J 7.6 Hz),7.38 (1H, d J 7.5 Hz), 5.87 (1H, s br), 3.68 (3H, s), 3.58 (2H, s), 2.96(4H, t J 4.8 Hz), 2.51 (4H, s br), 2.10 (3H, s), 1.62 (3H, s). m/z (ES⁺,70V) 440.1 (MH⁺).

EXAMPLE DDD86318 3′-Pyrrolidin-1-ylmethyl-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the aldehyde of intermediate 14 (80 mg, 0.23 mmol),pyrrolidine (57.0 μl, 49 mg, 0.069 mmol) and sodiumtriacetoxyborohydride (146 mg, 0.069 mmol) in CHCl₃ (5.0 ml) at 50° C.for 24 h according to the method of example DDD86212 to give the titlecompound as a white solid (85 mg, 0.20 mmol, 87%). δH (CDCl₃, 300K) 7.78(2H, d J 8.4 Hz), 7.71 (2H, d J 8.3 Hz), 7.51 (2H, s br), 7.43 (2H, d J6.6 Hz), 5.76 (1H, s), 3.77 (2H, s br), 3.68 (3H, s), 2.64 (4 h, s br),2.08 (3H, s), 1.86 (4H, s br), 1.64 (3H, s). m/z (ES⁺, 70V) 425.1 (MH⁺).

EXAMPLE DDD864672,6-Dichloro-N-(5-isobutyl-1,3-dimethyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 23B (115 mg, 0.25 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh₃)₄(30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.4 ml), according to themethod of intermediate 11, to give the title compound as a yellow solid(50 mg, 0.09 mmol, 37%). δH (D-6 DMSO, 300K) 8.20, (1H, d, J 5.3 Hz),8.07 (2H, s), 7.16 (1H, s), 7.03 (1H, d, J 5.3 Hz), 3.59 (3H, s), 3.52(4H, m), 2.80 (4H, m), 2.21 (2H, d J 7.5 Hz), 1.98 (1H, m), 1.77 (3H,s), 0.75 (6H, d J 6.6 Hz). m/z (ES⁺, 70V) 537.2 (MH⁺).

EXAMPLE DDD864682,6-Dichloro-N-(3,5-dimethyl-isoxazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 7 (100 mg, 0.25 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (87 mg, 0.30mmol), tribasic potassium phosphate (72 mg, 0.34 mmol), and Pd(PPh₃)₄(30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.4 ml), according to themethod of intermediate 11, to give the title compound as a yellow solid(12 mg, 0.025 mmol, 10%). δH (D-6 DMSO, 300K) 8.20, (1H, d J 5.3 Hz),7.94 (2H, s), 7.21 (1H, s), 7.08 (1H, d J 5.3 Hz), 3.65 (4H, m), 2.97(4H, m), 1.96 (3H, s), 1.91 (3H, s). m/z (ES⁺, 70V) 482.1 (MH⁺).

EXAMPLE DDD864692,6-Dichloro-4-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl]N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 2 (355 mg, 0.86 mmol),1-methyl-4-prop-2-ynyl-piperazine (142 mg, 1.03 mmol), CuI (8.2 mg,0.043 mmol) and Pd(PPh₃)₄ (50 mg, 0.043 mmol), in DMF (3.0 ml) and NEt₃(2.0 ml) according to the method of intermediate 36, to give the titlecompound as an off-white solid (150 mg, 0.32 mmol, 37%). δH (CDCl₃,300K) 7.47 (2H, s), 6.58 (1H, s), 3.67 (3H, s), 3.56 (2H, s), 2.67 (4H,s br), 2.51 (4H, s br), 2.32 (3H, s br), 2.13 (3H, s), 1.78 (3H, s). m/z(ES⁺, 70V) 470.1 (MH⁺).

EXAMPLE DDD864702,6-Dichloro-N-(3,5-dimethyl-isoxazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

Prepared from the boronic ester of intermediate 35 (184 mg, 0.4 mmol),4-(3-bromophenyl)piperidine hydrochloride (133 mg, 0.48 mmol), tribasicpotassium phosphate (144 mg, 0.68 mmol), and Pd(PPh₃)₄ (48 mg, 0.042mmol) in DMF (3.2 ml) and water (0.8 ml), according to the method ofintermediate 11, to give the title compound as a yellow solid (20 mg,0.040 mmol, 16%). δH (CDCl₃, 300K) 7.63 (2H, s), 7.41 (3H, m), 7.33 (1H,d J 6.6 Hz), 3.68 (3H, s), 3.23 (2H, d J 12.0 Hz), 2.78 (2H, dt J 12.1Hz 2.1 Hz), 2.71 (1H, tt J 12.1 Hz 3.6 Hz), 2.18 (3H, s), 1.88 (2H, d J12.6 Hz), 1.73 (3H, s), 1.70 (2H, qd J 12.5 Hz 3.8 Hz). m/z (ES⁺, 70V)493.1 (MH⁺).

EXAMPLE DDD86471N-(1,3-Dimethyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 28 (83 mg, 0.25 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh₃)₄(30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to themethod of intermediate 11, to give the title compound as a white solid(48 mg, 0.12 mmol, 47%). δH (D-6 DMSO, 300K) 8.20 (1H, d J 5.2 Hz), 7.95(2H, d J 8.3 Hz), 7.74 (2H, d J 8.3 Hz), 7.41 (1H, s), 7.08 (1H, s),6.97 (1H, d J 5.2 Hz), 3.65 (3H, s), 3.50 (4H, m), 2.80 (4H, m), 1.70(3H, s). m/z (ES⁺, 70V) 413.2 (MH⁺).

EXAMPLE DDD86474N-(1-Methyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 30 (79 mg, 0.25 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh₃)₄(30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to themethod of intermediate 11, to give the title compound as a white solid(46 mg, 0.12 mmol, 47%). δH (D-6 DMSO, 300K) 8.19 (1H, d J 5.2 Hz), 7.93(2H, d J 8.4 Hz), 7.78 (2H, d J 8.4 Hz), 7.49 (1H, s), 7.06 (2H, s),6.95 (1H, d J 5.2 Hz), 3.71 (3H, s), 3.49 (4H, m), 2.79 (4H, m). m/z(ES⁺, 70V) 399.2 (MH⁺).

EXAMPLE DDD864752,6-Dichloro-N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 29 (100 mg, 0.25 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh₃)₄(30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to themethod of intermediate 11, to give the title compound as a white solid(14 mg, 0.03 mmol, 12%). δH (D-6 DMSO, 300K) 8.16 (1H, d J 5.2 Hz), 7.97(2H, s), 7.41 (1H, s), 7.12 (1H, s), 7.00 (1H, d J 5.2 Hz), 3.60 (3H,s), 3.50 (4H, m), 2.77 (4H, m), 1.84 (3H, s). m/z (ES⁺, 70V) 481.1(MH⁺).

EXAMPLE DDD864782,6-Dichloro-N-(1-methyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 31 (96 mg, 0.25 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh₃)₄(30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to themethod of intermediate 11, to give the title compound as a yellow solid(87 mg, 0.19 mmol, 74%). δH (D-6 DMSO, 300K) 8.19 (1H, d J 5.2 Hz), 7.99(2H, s), 7.49 (1H, s), 7.14 (1H, s), 7.13 (1H, s), 7.02 (1H, d J 5.2Hz), 3.70 (3H, s), 3.54 (4H, m), 2.83 (4H, m). m/z (ES⁺, 70V) 467.1(MH⁺).

EXAMPLE DDD86479 3,5-Dichloro-3′-piperazin-1-yl-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the boronic ester of intermediate 35 (115 mg, 0.25 mmol),1-(3-bromophenyl)piperazine (72 mg, 0.48 mmol), tribasic potassiumphosphate (72 mg, 0.34 mmol), and Pd(PPh₃)₄ (30 mg, 0.026 mmol) in DMF(1.6 ml) and water (0.4 ml), according to the method of intermediate 11,to give the title compound as a yellow solid (21 mg, 0.042 mmol, 17%).δH (CDCl₃, 300K) 7.67 (2H, s), 7.39 (1H, t J 7.8 Hz), 7.04 (3H, m), 3.70(3H, s), 3.25 (4H, m), 3.09 (4H, m), 2.19 (3H, s), 1.81 (3H, s). m/z(ES⁺, 70V) 494.1 (MH⁺).

EXAMPLE DDD864802,6-Dichloro-N-(2-methyl-pyridin-3-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 9 (100 mg, 0.25 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (87 mg, 0.30mmol), tribasic potassium phosphate (180 mg, 0.85 mmol), and Pd(PPh₃)₄(30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to themethod of intermediate 11, to give the title compound as a tan colouredsolid (37 mg, 0.077 mmol, 31%). δH (D-6 DMSO, 300K) 8.18 (1H, d J 5.3Hz), 7.78 (2H, s), 7.64 (1H, d J 4.5 Hz), 7.31 (1H, d J 7.7 Hz), 7.15(1H, s), 7.13 (1H, s), 7.02 (1H, d J 4.7 Hz), 6.79 (1H, dd J 8.1 Hz 4.6Hz), 3.70 (4H, m), 3.05 (4H, m), 2.29 (3H, s). m/z (ES⁺, 70V) 478.1(MH⁺).

EXAMPLE DDD864812,6-Dichloro-N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 23A (115 mg, 0.25 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh₃)₄(30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.4 ml), according to themethod of intermediate 11, to give the title compound as a yellow solid(73 mg, 0.14 mmol, 54%). δH (D-6 DMSO, 300K) 8.20, (1H, d J 5.2 Hz),8.06 (2H, s), 7.15 (1H, s), 7.02 (1H, d J 5.2 Hz), 3.60 (3H, s), 3.52(4H, m), 2.80 (4H, m), 1.98 (3H, s), 1.92 (2H, d J 7.3 Hz), 1.70 (1H,m), 0.70 (6H, d J 6.6 Hz). m/z (ES⁺, 70V) 537.2 (MH⁺).

EXAMPLE DDD87748(34-[2-(3-Methyl-piperazin-1-yl)-pyridin-4-yl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the compound of intermediate 11 (250 mg, 0.66 mmol) and2-methyl piperazine (500 mg, 5.0 mmol) in EtOH (0.75 ml) according tothe method of DDD86213 to give the title compound as a white powder (157mg, 0.36 mmol, 55%). δH (D-6 DMSO, 300K) 9.21 (1H, s), 8.23 (1H, d J 5.2Hz), 8.01 (2H, d J 8.4 Hz), 7.74 (2H, d J 8.4 Hz), 7.13 (1H, s), 7.00(1H, d J 5.2 Hz), 4.28 (2H, t J 13.3 Hz), 3.60 (3H, s), 3.00 (1H, d J9.6 Hz), 2.80-2.68 (3H, m), 2.39 (1H, t J 11.3 Hz), 1.88 (3H, s), 1.63(3H, s), 1.08 (3H, d J 6.2 Hz). m/z (ES⁺, 70V) 441.2 (MH⁺).

EXAMPLE DDD877494-(3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4′-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the compound of intermediate 11 (250 mg, 0.66 mmol) andpiperidine (500 mg, 5.7 mmol) in EtOH (0.75 ml) according to the methodof DDD86213 to give the title compound as a white powder (189 mg, 0.44mmol, 67%). δH (D-6 DMSO, 300K) 9.20 (1H, s), 8.19 (1H, d J 5.2 Hz),7.96 (2H, d J 8.4 Hz), 7.74 (2H, d J 8.4 Hz), 7.13 (1H, s), 6.96 (1H, dJ 5.2 Hz), 3.68-3.62 (4H, m), 3.61 (3H, s), 1.87 (3H, s), 1-70-1.55 (6H,M), 1.63 (3H, s). m/z (ES⁺, 70V) 426.2 (MH⁺).

EXAMPLE DDD87751 3′-(2-Hydroxy-ethyl)-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the sulphonamide of Intermediate 1 (1.0 g, 2.91 mmol),3-hydroxyethylphenyl boronic acid (579 mg, 3.49 mmol), tribasicpotassium phosphate (740 mg, 3.49 mmol), Pd(dppf)Cl₂.DCM (119 mg, 0.146mmol) and water (2.0 ml) in oxygen-free DMF (10.0 ml) at 130° C. for 1 haccording to the method of intermediate 11, to give the title compoundas a colourless solid (500 mg, 1.30 mmol, 45%). δH (CDCl₃, 300K) 7.78(2H, d J 8.3 Hz), 7.68 (2H, d J 8.4 Hz), 7.49-7.47 (2H, m), 7.43 (1H, tJ 8.4 Hz), 7.30 (1H, d J 7.4 Hz), 5.79 (1H, s br), 3.93 (2H, q J 6.3Hz), 3.68 (3H, s), 2.96 (3H, t J 6.5 Hz), 2.09 (3H, s), 1.61 (3H, s),1.44 (1H, t J 5.8 Hz). m/z (ES⁺, 70V) 386.2 (MH⁺).

EXAMPLE DDD877533′-[2-(4-Methyl-piperazin-1-yl)-ethyl]-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

The compound of example DDD87751 (400 mg, 1.04 mmol) and triethylamine(218 μl, 158 mg, 1.56 mmol) in DCM (3.0 ml) at rt was treated dropwisewith methanesulfonylchloride (97 μl, 143 mg, 1.25 mmol) and the reactionstirred for 21 h. The mixture was then diluted with DCM (40.0 ml) andthe organic layer washed with H₂O (2×10 ml), dried over MgSO₄ andconcentrated in vacuo to yield the crude methanesulfonate intermediateas an off-white solid (460 mg, 0.99 mmol, 95%). δH (CDCl₃, 300K) 7.81(2H, d J 8.6 Hz), 7.67 (2H, d J 8.6 Hz), 7.52-7.42 (3H, m), 7.33-7.26(1H, m), 5.76 (1H, s br), 4.48 (2H, t J 6.9 Hz), 3.69 (3H, s), 3.15 (2H,t J 6.5 Hz), 2.92 (3H, s), 2.10 (3H, s), 1.55 (3H, s). m/z (ES⁺, 70V)464.1 (MH⁺).

A mixture of the above methanesulfonate (150 mg, 0.32 mmol), sodiumcarbonate (102 mg, 0.96 mmol) and N-methyl piperazine (106 μl, 96 mg,0.96 mmol) in CH₃CN (2.0 ml) was heated in a microwave at 120° C. for 30min. The crude mixture was then filtered through an SCX-2 column whichwas washed with DCM:MeOH (10:1, 20.0 ml), followed by elution with 7MNH₃ in MeOH (20.0 ml). The eluted fraction was concentrated in vacuo andsubjected to chromatography (4-10% MeOH:DCM) to give the title compoundas a colourless solid (90 mg, 0.21 mmol, 50%). δH (CDCl₃, 300K) 7.78(2H, d J 8.5 Hz), 7.67 (2H, d J 8.5 Hz), 7.49-7.47 (2H, m), 7.45-7.43(2H, m), 7.40 (1H, t J 7.40 Hz), 7.28 (1H, s br), 5.79 (1H, s br), 3.68(3H, s), 2.89 (2H, t J 7.7 Hz), 2.66 (2H, t J 8.4 Hz), 2.65-2.32 (4H,m), 2.33 (3H, s br), 2.09 (3H, s), 1.60 (7H, s br). m/z (ES⁺, 70V) 468.2(MH⁺).

EXAMPLE DDD87754 3′-(3-Phenyl-piperazin-1-ylmethyl)-biphenyl-4-sulfonicacid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the aldehyde of intermediate 14 (200 mg, 0.54 mmol),2-phenylpiperazine (262 mg, 1.62 mmol) and sodium triacetoxyborohydride(343 mg, 1.62 mmol) in CHCl₃ (12.0 ml) at 50° C. for 24 h according tothe method of example DDD86212 to give the title compound as a whitesolid (200 mg, 0.39 mmol, 72%). δH (CDCl₃, 300K) 7.78 (2H, d J 8.5 Hz),7.69 (2H, d J 8.5 Hz), 7.58 (1H, s br), 7.49 (1H, d J 7.4 Hz), 7.42 (2H,t J 7.5 Hz), 7.38 (2H, dd J 1.5 Hz 7.3 Hz), 7.31 (2H, t J 7.1 Hz) 7.27(1H, t J 1.3 Hz), 5.80 (1H, s br), 3.93 (1H, dd J 2.3 Hz 10.0 Hz), 3.69(3H, s), 3.63 (2H, s), 3.14-3.08 (2H, m), 2.94 (1H, d J 10.6 Hz), 2.89(1H, d J 11.1 Hz), 2.42 (1H, s br), 2.28 (1H, dt 3.5 Hz 7.4 Hz), 2.16(1H, t J 10.7 Hz), 2.09 (3H, s), 1.61 (3H, s). m/z (ES⁺, 70V) 515.2(MH⁺).

EXAMPLE DDD87755N-(3-Hydroxy-propyl)-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 21 (300 mg, 0.7 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (216 mg, 0.7mmol), tribasic potassium phosphate (158 mg, 0.7 mmol), Pd(PPh₃)₄ (50mg, 0.04 mmol) and water (1.0 ml) in oxygen-free DMF (5.0 ml) at 130° C.for 1 h, according to the method of intermediate 11 except with the useof Pd(PPh₃)₄ as reaction catalyst, to give the title compound as a whitesolid (100 mg, 0.2 mmol, 26%). δH (D-6 DMSO, 300K) 9.36 (2H, s br), 8.26(1H, d J 5.6 Hz), 8.08 (2H, d J 8.4 Hz), 7.81 (2H, d J 8.4 Hz), 7.43(1H, s), 7.23 (1H, d J 5.6 Hz), 3.99-3.92 (4H, m), 3.68-3.63 (1H, m),3.63 (3H, s), 3.46-3.41 (3H, m), 3.27-3.21 (4H, m), 1.89 (3H, s), 1.57(3H, s), 1.58-1.52 (2H, m). m/z (ES⁺, 70V) 485.2 (MH⁺).

EXAMPLE DDD877564-[2-(3-Phenyl-piperazin-1-yl)-pyridin-4-yl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the compound of intermediate 11 (250 mg, 0.66 mmol) and2-phenyl piperazine (500 mg, 3.1 mmol) in EtOH (0.75 ml) according tothe method of DDD86213 to give the title compound as a white powder (182mg, 0.36 mmol, 55%). δH (D-6 DMSO, 300K) 9.24 (1H, s br), 8.25 (1H, d J5.2 Hz), 8.01 (2H, d J 8.4 Hz), 7.73 (2H, d J 8.4 Hz), 7.54 (2H, d J 7.4Hz), 7.41 (2H, t J 7.35 Hz), 7.34 (1H, t J 7.35 Hz), 7.18 (1H, s), 7.03(1H, d J 5.3 Hz), 4.42-4.39 (31-1, m), 3.81-3.78 1H, m), 3.60 (3H, s),3.14 (1H, d J 8.8 Hz), 2.93-2.89 (3H, m), 2.70 (1H, t J 11.8 Hz), 1.87(3H, s), 1.63 (3H, s). m/z (ES⁺, 70V) 503.1 (MH⁺).

EXAMPLE DDD87758 2′-Diethylaminomethyl-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the aldehyde of intermediate 17 (150 mg, 0.41 mmol),diethylamine (127 μl, 90 mg, 1.23 mmol) and sodium triacetoxyborohydride(261 mg, 1.23 mmol) in CHCl₃ (10.0 ml) at 50° C. for 24 h according tothe method of example DDD86212 to give the title compound as a whitesolid (106 mg, 0.25 mmol, 62%). δH (CDCl₃, 300K) 7.76 (2H, d J 8.2 Hz),7.63 (1H, s br), 7.47 (2H, d J 8.4 Hz), 7.38 (1H, t J 7.0 Hz), 7.31 (1H,t J 7.1 Hz), 7.15 (1H, d J 7.7 Hz), 5.79 (1H, s br), 3.69 (3H, s), 3.41(2H, m), 2.40 (4H, d J 5.6 Hz), 2.13 (3H, s), 1.63 (3H, s), 0.90 (6H, tJ 6.5 Hz). m/z (ES⁺, 70V) 427.2 (MH⁺).

EXAMPLE DDD87759 2′-Pyrrolidin-1-ylmethyl-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the aldehyde of intermediate 17 (150 mg, 0.41 mmol),pyrrolidine (101 μl, 87 mg, 1.23 mmol) and sodium triacetoxyborohydride(261 mg, 1.23 mmol) in CHCl₃ (10.0 ml) at 50° C. for 24 h according tothe method of example DDD86212 to give the title compound as a whitesolid (166 mg, 0.39 mmol, 95%). δH (CDCl₃, 300K) 7.78 (2H, d J 8.2 Hz),7.54 (3H, d J 7.3 Hz), 7.41 (1H, d J 5.9 Hz), 7.35 (1H, m), 7.21 (1H, dJ 7.5 Hz), 5.81 (111, s br), 3.69 (3H, s), 3.55 (2H, s br), 2.45 (4H, sbr), 2.13 (3H, s br), 1.76 (4H, s br), 1.62 (3H, s). m/z (ES⁺, 70V)454.1 (MH⁺).

EXAMPLE DDD877614-[2-(3,5-Dimethyl-piperazin-1-yl)-pyridin-4-yl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the compound of intermediate 11 (250 mg, 0.66 mmol) and2,6-dimethylpiperazine (>95% syn isomer, 500 mg, 4.38 mmol) in EtOH(0.75 ml) according to the method of DDD86213 to give the title compoundas a white powder (211 mg, 0.46 mmol, 70%). δH (D-6 DMSO, 300K) 9.22(1H, s), 8.18 (1H, d J 4.0 Hz), 7.97 (2H, d J 7.7 Hz), 7.70 (2H, d J 7.7Hz), 7.10 (1H, s), 6.95 (1H, s), 4.30 (2H, d J 11.8 Hz), 3.56 (3H, s),2.76 (2H, s br), 2.26 (2H, t J 11.3 Hz), 1.84 (3H, s), 1.59 (3H, s),1.04 (6H, d J 4.8 Hz). m/z (ES⁺, 70V) 455.2 (MH⁺).

EXAMPLE DDD87763N-Methyl-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of Intermediate 18 (250 mg, 0.7 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (202 mg, 0.7mmol), tribasic potassium phosphate (148 mg, 0.7 mmol), Pd(PPh₃)₄ (50mg, 0.04 mmol) and water (1.0 ml) in oxygen-free DMF (5.0 ml) at 130° C.for 1 h, according to the method of intermediate 11 except with the useof Pd(PPh₃)₄ as reaction catalyst, to give the title compound as a whitesolid (148 mg, 0.3 mmol, 48%). δH (CDCl₃, 300K) 8.28 (1H, d, J 3.8 Hz),7.79 (2H, d, J 7.2 Hz), 7.71 (2H, d, J 7.2 Hz), 6.82 (1H, d, J 3.8 Hz),6.79 (1H, s), 3.69 (3H, s), 3.57-3.61 (4H, m), 3.21 (3H, s), 2.99-3.04(4H, m), 2.13 (3H, s), 1.55 (3H, s). m/z (ES⁺, 70V) 441.2 (MH⁺).

EXAMPLE DDD87764 2′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-sulfonicacid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the aldehyde of intermediate 17 (150 mg, 0.41 mmol),N-methylpiperazine (136 μl, 123 mg, 1.23 mmol) and sodiumtriacetoxyborohydride (261 mg, 1.23 mmol) in CHCl₃ (10.0 ml) at 50° C.for 24 h according to the method of example DDD86212 to give the titlecompound as a colourless solid (150 mg, 0.33 mmol, 81%). δH (CDCl₃,300K) 7.75 (2H, d J 8.4 Hz), 7.58 (2H, d J 8.3 Hz), 7.45 (1H, d J 5.9Hz), 7.39-7.33 (2H, m), 7.22 (1H, dd J 1.6 Hz 7.3 Hz), 5.79 (1H, s br),3.69 (3H, s), 3.33 (2H, s), 2.42 (4H, s br), 2.31 (3H, s br), 2.11 (3H,s), 1.98 (4H, s br), 1.64 (3H, s). m/z (ES⁺, 70V) 454.1 (MH⁺).

EXAMPLE DDD87765 3′-(Benzylamino-methyl)-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the aldehyde of intermediate 14 (200 mg, 0.54 mmol),benzylamine (176 μl, 173 mg, 1.62 mmol) and sodium triacetoxyborohydride(343 mg, 1.62 mmol) in CHCl₃ (12.0 ml) at 50° C. for 24 h according tothe method of example DDD86212 to give the title compound as a whitesolid (105 mg, 0.23 mmol, 42%). δH (CDCl₃, 300K) 7.78 (2H, d J 8.4 Hz),7.69 (2H, d J 8.4 Hz), 7.60 (1H, s br), 7.50 (1H, d J 7.5 Hz), 7.44 (1H,t J 7.5 Hz), 7.40 (1H, d J 7.6 Hz), 7.35 (4H, d J 4.8 Hz), 7.29-7.28(1H, m), 5.85 (1H, s br), 3.90 (2H, s br), 3.86 (2H, s br), 3.68 (3H,s), 2.08 (3H, s), 1.62 (3H, s). m/z (ES⁺, 70V) 461.1 (MH⁺).

EXAMPLE DDD877674-(2-[1,4]Diazepan-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared by heating the compound of intermediate 11 (250 mg, 0.66 mmol)and homopiperazine (500 mg, 5.0 mmol) in EtOH (1.0 ml) at 155° C. for 2h, according to the method of DDD86213 to give the title compound as awhite powder (207 mg, 0.47 mmol, 71%). δH (D-6 DMSO, 300K) 8.20 (1H, d J5.8 Hz), 7.99 (2H, d J 8.5 Hz), 7.75 (2H, d J 8.5 Hz), 6.90 (1H, s),6.89 (1H, d J 5.8 Hz), 3.80 (2H, t J 6.1 Hz), 3.75 (2H, t J 5.8 Hz),2.92 (2H, t J 5.2 Hz), 2.72 (2H, t J 5.6 Hz), 1.88 (3H, s), 1.83 (2H, pJ 5.6 Hz), 1.63 (3H, s). m/z (ES⁺, 70V) 441.2 (MH⁺).

EXAMPLE DDD87768 3′-Piperidin-4-yl-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the sulphonamide of intermediate 32 (500 mg, 1.28 mmol),4-(3-bromophenyl)piperidine hydrochloride (425 mg, 1.54 mmol), tribasicpotassium phosphate (652 mg, 3.0 mmol), and Pd(dppf)Cl₂.DCM (100 mg,0.12 mmol) in DMF (3.0 ml) and water (0.75 ml), according to the methodof intermediate 11, to give the title compound as an off-white powder(350 mg, 0.82 mmol, 64%). δH (D-6 DMSO, 300K) 7.90 (2H, d J 8.4 Hz),7.71 (2H, d 8.4 Hz), 7.61 (1H, s), 7.58 (1H, d J 7.9 Hz), 7.46 (1H, t J7.7 Hz), 7.33 (1H, d J 7.7 Hz), 3.58 (3H, s), 3.10-3.07 (2H, m br), 2.70(1H, tt J 12.1 Hz 3.3 Hz), 2.63 (2H, td 10.8 Hz 1.8 Hz), 1.85 (3H, s),1.79-1.73 (2H, m br), 1.63 (3H, s), 1.62 (qd J 12.2 Hz 3.8 Hz). m/z(ES⁺, 70V) 425.2 (MH⁺).

EXAMPLE DDD877692,6-Dichloro-4-[3-(4-methyl-piperazin-1-yl)-propyl]N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

The alkyne of example DDD86469 (65 mg, 0.14 mmol) and 10% w/w palladiumon charcoal (13 mg, 20 wt %) in MeOH (7.0 ml) was stirred at rt underfor 1.5 h. The mixture was filtered through a celite pad, the filtercake washed with DCM:MeOH (1:1, 2×10 ml), the combined filtratesconcentrated in vacuo and subjected to chromatography (4-10% MeOH/DCM)to give the title compound as a white solid (28 mg, 0.059 mmol, 42%). δH(CDCl₃, 300K) 7.29 (2H, s), 6.58 (1H, s), 3.66 (3H, s), 2.63 (2H, s br),2.47 (6H, s), 2.31 (3H, s), 2.16 (3H, s) 1.79 (2H, s br), 1.72 (3H, s),1.59 (4H, s br). m/z (ES⁺, 70V) 474.1 (MH⁺).

EXAMPLE DDD879932,6-Dichloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 27 (100 mg, 0.25 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh₃)₄(30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to themethod of intermediate 11, to give the title compound as a yellow solid(32 mg, 0.07 mmol, 27%). δH (D-6 DMSO, 300K) 8.20 (1H, d J 5.2 Hz), 8.02(2H, s), 7.20 (1H, s), 7.04 (1H, d J 5.2 Hz), 7.02 (1H, s), 3.64 (3H,s), 3.54 (4H, m), 2.82 (4H, m), 2.06 (3H, s). m/z (ES⁺, 70V) 481.1(MH⁺).

EXAMPLE DDD87994N-(2-Methyl-pyridin-3-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 8 (82 mg, 0.25 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh₃)₄(30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to themethod of intermediate 11, to give the title compound as a yellow solid(13 mg, 0.03 mmol, 13%). δH (D-6 DMSO, 300K) 8.20 (1H, d J 5.3 Hz), 8.01(1H, d J 4.2 Hz), 7.90 (2H, d J 8.3 Hz), 7.75 (2H, d J 8.3 Hz), 7.36(1H, dd J 8.1 Hz 1.1 Hz), 7.11 (1H, s), 7.03 (1H, dd J 8.0 Hz 4.8 Hz),6.99 (1H, d J 5.2 Hz), 3.62 (4H, m), 2.96 (4H, m), 2.21 (3H, s). m/z(ES⁺, 70V) 410.2 (MH⁺).

EXAMPLE DDD87995N-(1,5-Dimethyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 27 (83 mg, 0.25 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh₃)₄(30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to themethod of intermediate 11, to give the title compound as a yellow solid(22 mg, 0.05 mmol, 21%). δH (D-6 DMSO, 300K) 8.21 (1H, d J 5.2 Hz), 7.96(2H, d J 8.4 Hz), 7.75 (2H, d 8.4 Hz), 7.09 (1H, s), 6.98 (1H, d J 5.2Hz), 6.91 (1H, s), 4.13 (1H, s br), 3.63 (3H, s), 3.52 (4H, m), 2.82(4H, m), 1.92 (3H, s). m/z (ES⁺, 70V) 413.2 (MH⁺).

EXAMPLE DDD879972,5-Difluoro-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from Intermediate 4 (200 mg, 0.5 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (152 mg, 0.5mmol), tribasic potassium phosphate (112 mg, 0.5 mmol), Pd(PPh₃)₄ (45mg, 0.04 mmol) and water (0.8 ml) in oxygen-free DMF (4.0 ml) at 130° C.for 1 h, according to the method of intermediate 11 except with the useof Pd(PPh₃)₄ as reaction catalyst, to give the title compound as a whitesolid (93 mg, 0.2 mmol, 38%). δH (CDCl₃, 300K) 8.28 (1H, d J 5.1 Hz),7.52 (1H, dd J 5.7 Hz 9.1 Hz), 7.34 (1H, dd J 5.6 Hz 9.8 Hz), 6.74-6.70(2H, m), 3.68 (3H, s), 3.59-3.54 (4H, m), 3.03-2.99 (4H, m), 2.18 (3H,s), 1.81 (3H, s). m/z (ES⁺, 70V) 463.2 (MH⁺).

EXAMPLE DDD879994-[3-(4-Methyl-piperazin-1-yl)-prop-1-ynyl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 1 (526 mg, 1.53 mmol),1-methyl-4-prop-2-ynyl-piperazine (253 mg, 1.83 mmol), CuI (15 mg, 0.077mmol) and Pd(PPh₃)₄ (89 mg, 0.077 mmol), in DMF (3.0 ml) and NEt₃ (2.0ml) according to the method of intermediate 36, to give the titlecompound as an off-white solid (390 mg, 0.97 mmol, 64%). δH (CDCl₃,300K) 7.66 (2H, d J 7.2 Hz), 7.47 (2H, d J 7.6 Hz), 5.85 (1H, s br),3.67 (3H, s), 3.67 (3H, s), 3.58 (2H, s), 2.84 (4H, s br), 2.48 (4H, sbr), 2.03 (3H, s br), 1.64 (3H, s br), 1.52 (3H, s). m/z (ES⁺, 70V)402.1 (MH⁺).

EXAMPLE DDD880006-[2-(1-Methyl-piperidin-4-yl)-ethylamino]-pyridine-3-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the sulphonamide of intermediate 5 (528 mg, 1.8 mmol) and2-(1-methylpiperidin-4-yl)ethanamine (500 mg, 3.5 mmol) according tomethod 1 of EXAMPLE 86213, to give the title compound as a white solid(190 mg, 0.5 mmol, 27%). δH (CDCl₃, 300K) 8.38 (1H, d, J 2.3 Hz), 7.60(1H, dd J 2.3 Hz 9.0 Hz), 6.31 (1H, d J 9.0 Hz), 5.80 (1H, s), 4.97 (1H,bs), 3.68 (3H, s), 3.38-3.32 (2H, m), 2.87-2.81 (2H, m), 2.26 (3H, s),2.12 (3H, s), 1.93-1.85 (2H, m), 1.73 (3H, s), 1.74-1.68 (2H, m),1.63-1.54 (3H, m), 1.31-1.37 (2H, m). m/z (ES⁺, 70V) 407.2 (MH⁺)

EXAMPLE DDD88002N-(3,5-Dimethyl-isoxazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 6 (83 mg, 0.25 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh₃)₄(30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.4 ml), according to themethod of intermediate 11, to give the title compound as a tan colouredsolid (11 mg, 0.03 mmol, 11%). δH (D-6 DMSO, 300K) 8.20, (1H, d J 5.3Hz), 7.99 (2H, d J 8.4 Hz), 7.75 (2H, d J 8.4 Hz), 7.10 (1H, s), 6.98(1H, dd J 5.2 Hz 1.1 Hz), 3.53 (4H, m), 2.83 (4H, m), 1.93 (3H, m), 1.80(3H, s). m/z (ES⁺, 70V) 482.1 (MH⁺).

EXAMPLE DDD88003 3′-Piperidin-4-yl-biphenyl-4-sulfonic acid(2-methyl-pyridin-3-yl)-amide

Prepared from the sulphonamide of intermediate 33 (230 mg, 0.62 mmol),4-(3-bromophenyl)piperidine hydrochloride (204 mg, 0.74 mmol), tribasicpotassium phosphate (313 mg, 1.48 mmol), and Pd(dppf)Cl₂.DCM (50 mg,0.06 mmol) in DMF (3.0 ml) and water (1.0 ml), according to the methodof intermediate 11, to give the title compound as an off-white powder(67 mg, 0.16 mmol, 26%). δH (CDCl₃, 300K) 8.35 (1H, dd J 1.3 Hz 4.7 Hz),7.76 (2H, d J 8.5 Hz), 7.75 (1H, m), 7.43-7.38 (3H, m), 7.28 (1H, m),7.15 (1H, dd J 4.7 Hz 8.0 Hz), 3.23-3.18 (2H, m), 2.76 (2H, td J 2.1 Hz12.1 Hz), 2.68 (1H, tt J 3.6 Hz 12.1 Hz), 2.22 (3H, s), 1.89-1.83 (2H, mbr), 1.69 (2H, qd J 12.1 Hz 3.9 Hz). m/z (ES⁺, 70V) 408.2 (MH⁺).

EXAMPLE DDD88005 3′-Dimethylaminomethyl-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the aldehyde of intermediate 14 (150 mg, 0.41 mmol), 2Mdimethylamine solution in THF (615 ml, 1.23 mmol) and sodiumtriacetoxyborohydride (261 mg, 1.23 mmol) in CHCl₃ (10.0 ml) at 50° C.for 24 h according to the method of example DDD86212 to give the titlecompound as a white solid (146 mg, 0.37 mmol, 90%). δH (CDCl₃, 300K)7.78 (2H, d J 6.9 Hz), 7.70 (2H, d J 7.5 Hz), 7.60 (1H, s br), 7.49 (1H,d J 6.8 Hz), 7.42 (1H, t J 7.8 Hz), 7.36 (1H, d J 6.7 Hz), 5.81 (1H, sbr), 3.68 (3H, s), 3.59 (2H, s), 2.33 (6H, s), 2.08 (3H, s), 1.62 (3H,s). m/z (ES⁺, 70V) 399.3 (MH⁺).

EXAMPLE DDD88006 3′-imidazol-1-ylmethyl-biphenyl-4-sulfonic acid(1,3,6-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the boronic ester of intermediate 32 (157 mg, 0.38 mmol),1-(3-bromobenzyl)-1H-imidazole (114 mg, 0.48 mmol), tribasic potassiumphosphate (144 mg, 0.68 mmol), and Pd(PPh₃)₄ (48 mg, 0.042 mmol) in DMF(1.6 ml) and water (0.4 ml), according to the method of intermediate 11,to give the title compound as a white solid (157 mg, 0.37 mmol, 93%). δH(D-6 DMSO, 300K) 7.84 (3H, m), 7.73-7.60 (4H, m), 7.59 (1H, m), 7.50(1H, t J 7.7 Hz), 7.30 (1H, d J 7.7 Hz), 7.27 (1H, s), 6.92 (1H, s),5.28 (2H, s), 3.56 (3H, s), 1.82 (3H, s), 1.59 (3H, s). m/z (ES⁺, 70V)422.2 (MH⁺).

EXAMPLE DDD88007 3,5-Dichloro-3′-diethylaminomethyl-biphenyl-4-sulfonicacid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the sulphonamide of intermediate 15 (210 mg, 0.52 mmol),diethylamine (0.25 ml), sodium triacetoxyborohydride (220 mg, 1.04 mmol)in chloroform (3.0 ml), according to the method of example DDD85612, togive the title compound as an off-white powder (39 mg, 0.08 mmol, 15%).δH (CDCl₃, 300K) 7.65 (2H, s), 7.53 (1H, s), 7.43-7.37 (3H, m), 6.62(1H, s), 3.64 (3H, s), 3.60 (2H, s), 2.52 (4H, q J 6.8 Hz), 2.14 (3H,s), 1.77 (3H, s), 1.03 (6H, t J 6.8 Hz). m/z (ES⁺, 70V) 495.1 (MH⁺).

EXAMPLE DDD880093,5-Dichloro-3′-pyrrolidin-1-ylmethyl-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the sulphonamide of intermediate 15 (210 mg, 0.52 mmol),pyrolidine (0.25 ml) and sodium triacetoxyborohydride (220 mg, 1.04mmol) in chloroform (3.0 ml), according to the method of exampleDDD85612, to give the title compound as an off-white powder (172 mg,0.35 mmol, 67%). δH (CDCl₃, 300K) 7.65 (2H, s), 7.52 (1H, s), 7.45-7.37(3H, m), 6.72 (1H, s br), 3.67 (2H, s), 3.64 (3H, s), 2.50 (4H, s br),2.12 (3H, s), 1.77 (4H, s br), 1.73 (3H, s). m/z (ES⁺, 70V) 493.1 (MH⁺).

EXAMPLE DDD881862-Methyl-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 20 (90 mg, 0.25 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh₃)₄(30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to themethod of intermediate 11, to give the title compound as a yellow solid(47 mg, 0.11 mmol, 43%). δH (D-6 DMSO, 300K) 8.20 (1H, d J 5.1 Hz), 7.84(1H, s), 7.70 (1H, dd J 8.3 Hz 1.5 Hz), 7.64 (1H, d J 8.3 Hz), 7.10 (1H,s), 6.99 (1H, dd J 5.2 Hz 1.2 Hz), 3.55 (7H, m), 2.87 (4H, m), 2.65 (3H,s), 1.84 (3H, s), 1.58 (3H, s). m/z (ES⁺, 70V) 441.2 (MH⁺).

EXAMPLE DDD881875′-(4-Methyl-piperazin-1-ylmethyl)-3′-propoxy-biphenyl-4-sulfonic acid(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the aldehyde of intermediate 24 (150 mg, 0.35 mmol),N-methylpiperazine (0.116 ml, 105 mg, 1.05 mmol) and sodiumtriacetoxyborohydride (223 mg, 1.05 mmol) in CHCl₃ (10.0 ml) at 50° C.for 24 h according to the method of example DDD86212 to give the titlecompound as a white solid (143 mg, 0.28 mmol, 80%). δH (CDCl₃, 300K)7.76 (2H, d J 8.4 Hz), 7.67 (2H, d J 8.4 Hz), 7.13 (1H, s br), 7.00 (1H,s br), 6.95 (1H, s br), 5.74 (1H, s br), 3.98 (2H, t J 6.6 Hz), 3.68(3H, s), 3.54 (2H, s), 2.49 (4H, s br), 2.30 (3H, s), 2.09 (3H, s), 1.84(2H, m), 1.60 (7H, s), 1.07 (3H, t J 7.4 Hz). m/z (ES⁺, 70V) 512.2(MH⁺).

EXAMPLE DDD881882-Fluoro-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 10 (91 mg, 0.25 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (80 mg, 0.28mmol), tribasic potassium phosphate (60 mg, 0.28 mmol), and Pd(PPh₃)₄(30 mg, 0.026 mmol) in DMF (1.6 ml) and water (0.6 ml), according to themethod of intermediate 11, to give the title compound as a pale yellowsolid (25 mg, 0.056 mmol, 22%). δH (D-6 DMSO, 300K) 8.03 (1H, m), 7.57(2H, m), 7.46 (1H, d J 7.7 Hz), 6.90 (1H, s), 6.81 (1H, m), 3.46 (3H,s), 3.43 (4H, m), 2.78 (4H, m), 1.86 (3H, s), 1.65 (3H, s). m/z (ES⁺,70V) 445.2 (MH⁺)

EXAMPLE DDD88189 3′-Piperidin-4-yl-biphenyl-4-sulfonic acid(3,5-dimethyl-isoxazol-4-yl)-amide

Prepared from the sulphonamide of intermediate 34 (151 mg, 0.4 mmol),4-(3-bromophenyl)piperidine hydrochloride (133 mg, 0.48 mmol), tribasicpotassium phosphate (144 mg, 0.68 mmol), and Pd(PPh₃)₄ (48 mg, 0.042mmol) in DMF (3.2 ml) and water (0.8 ml), according to the method ofintermediate 11, to give the title compound as a white solid (19 mg,0.046 mmol, 12%). δH (D-6 DMSO, 300K) 7.00, (4H, s), 6.76 (1H, s), 6.74(1H, d J 7.7 Hz), 6.64 (1H, t J 6.6 Hz), 6.53 (1H, d J 6.9 Hz), 2.46(2H, d 12.0 Hz), 2.05 (3H, m), 1.25 (1H, s), 1.19 (3H, s), 1.15 (2H, m),1.10 (3H, s), 0.99 (2H, q, J 12.2 Hz). m/z (ES⁺, 70V) 412.2 (MH⁺).

EXAMPLE DDD881914-[3-(4-Methyl-piperazin-1-yl)-propyl]N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the alkyne of example DDD87999 (345 mg, 0.86 mmol) and 10%w/w palladium on charcoal (70 mg, 20 wt %) in MeOH (40 mL) for 2 haccording to the method of example DDD00087769 to give the titlecompound as a pale yellow solid (170 mg, 0.42 mmol, 49%). δH (CDCl₃,300K) 7.63 (2H, d J 8.3 Hz), 7.27-7.26 (2H, m), 5.72 (1H, s br), 3.67(3H, s), 2.71 (6H, t J 7.4 Hz), 2.44 (6H, m), 2.08 (3H, s), 1.85 (2H, sbr), 1.53 (6H, s), m/z (ES⁺, 70V) 406.2 (MH⁺).

EXAMPLE DDD000881932,6-Dichloro-N-methyl-4-(2-piperazin-1-yl-pyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of Intermediate 19 (225 mg, 0.5 mmol),2-(1-piperazinyl)pyridine-4-boronic acid pinacol ester (153 mg, 0.5mmol), tribasic potassium phosphate (112 mg, 0.5 mmol), Pd(PPh₃)₄ (30mg, 0.03 mmol) and water (0.5 ml) in oxygen-free DMF (3.0 ml) at 120° C.for 20 min, according to the method of intermediate 11, to give thetitle compound as a white solid (173 mg, 0.3 mmol, 64%). δH (D-6 DMSO,300K) 9.23 (2H, s br), 8.27 (1H, d J 5.3 Hz), 8.15 (2H, s), 7.42 (1H,s), 7.27 (1H, d J 5.3 Hz), 3.95-3.89 (4H, m br), 3.60 (3H, s), 3.36 (3H,s), 3.25-3.19 (4H, m br), 1.97 (3H, s), 1.76 (3H, s). m/z (ES⁺, 70V)509.1 (MH⁺).

EXAMPLE DDD881943′-Isopropoxy-5′-(4-methyl-piperazin-1-ylmethyl)-biphenyl-4-sulfonicacid (1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the aldehyde of intermediate 25 (150 mg, 0.35 mmol),N-methylpiperazine (0.116 ml, 105 mg, 1.05 mmol) and sodiumtriacetoxyborohydride (223 mg, 1.05 mmol) in CHCl₃ (10.0 ml) at 50° C.for 24 h according to the method of example DDD86212 to give the titlecompound as a colourless solid (120 mg, 0.23 mmol, 67%). δH (CDCl₃,300K) 7.76 (2H, d J 6.9 Hz), 7.66 (2H, d J 7.5 Hz), 7.11 (1H, s br),6.99 (1H, s br), 6.94 (1H, s br), 5.75 (1H, s br), 4.64 (1H, s br), 3.68(3H, s), 3.54 (2H, s), 2.49 (4H, s), 2.31 (3H, s), 2.09 (3H, s), 1.66(4H, m), 1.61 (3H, s), 1.37 (6H, d J 5.0 Hz). m/z (ES⁺, 70V) 512.2(MH⁺).

EXAMPLE DDD88195 3′-Diethylaminomethyl-biphenyl-4-sulfonic acidmethyl-(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the sulphonamide of intermediate 22 (85 mg, 0.2 mmol),diethylamine (49 mg, 0.7 mmol) and sodium triacetoxyborohydride (141 mg,0.7 mmol) in CHCl₃ (4 ml), according to the method of Example DDD86212to give the title compound as a white powder (19 mg, 0.043 mmol, 22%).δH (D-6 DMSO, 300K) 9.91 (1H, s br), 8.06 (1H, s), 8.00 (2H, d J 8.5Hz), 7.89-7.86 (1H, m), 7.81 (2H, d J 8.5 Hz), 7.66-7.61 (2H, m), 4.41(2H, d J 5.6 Hz), 3.62 (3H, s), 3.16 (3H, s), 3.17-3.08 (3H, m), 1.92(3H, s), 1.59 (3H, s), 1.28 (6H, t J 7.3 Hz). m/z (ES⁺, 70V) 441.2(MH⁺).

EXAMPLE DDD88196 3′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-sulfonicacid methyl-(1,3,5-trimethyl-1H-pyrazol-4-yl)-amide

Prepared from the sulphonamide of intermediate 22 (85 mg, 0.2 mmol),N-methylpiperazine (67 mg, 0.7 mmol) and sodium triacetoxyborohydride(141 mg, 0.7 mmol) in CHCl₃ (4 ml), according to the method of ExampleDDD86212 to give the title compound as a white powder (65 mg, 0.14 mmol,69%). δH (D-6 DMSO, 300K) 8.13 (1H, s br), 8.02 (2H, d J 7.4 Hz),7.89-7.84 (1H, m br), 7.79 (2H, d J 7.4 Hz), 7.69 (1H, s br), 7.62 (1H,s br), 4.57-4.34 (2H, m br), 3.62 (3H, s), 3.74-3.56 (4H, m br),3.52-3.27 (4H, m br), 3.16 (3H, s), 2.83 (3H, s br), 1.91 (3H, s), 1.60(3H, s). m/z (ES⁺, 70V) 468.2 (MH⁺).

EXAMPLE DDD864692,6-Dichloro-4-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide

Prepared from the sulphonamide of intermediate 19 (1.3 g, 3.06 mmol),4-(propyn-3-yl)-1-methyl piperazine (1.05 g, 7.61 mmol), CuI (50 mg,0.26 mmol) and Pd(PPh₃)₄ (100 mg, 0.08 mmol), in DMF (15 ml) and NEt₃ (8ml) according to the method of intermediate 36, to give the titlecompound as a white solid (1.25 g, 2.66 mmol, 87%). δH (CDCl3, 300K)7.43 (2H, s), 3.67 (3H, s), 3.54 (2H, s), 3.40 (3H, s), 2.73-2.60 (4H, sbr), 2.59-2.42 (4H, s br), 2.32 (3H, s), 2.06 (3H, s), 1.83 (3H, s). m/z(ES⁺, 70V) 470.2 (MH⁺).

EXAMPLE DDD99837N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-4-(3-(1-methylpiperidin-4-yl)propyl)benzenesulfonamide

Prepared from 4-allyl-1-methylpiperidine (2.18 g, 15.6 mmol) and thecompound of intermediate 41 (2.0 g, 5.2 mmol) according to the method ofcompound DDD100096 to give the title compound as a white powder (1.84 g,4.12 mmol, 79%). δH (CDCl₃, 300K), 7.55 (2H, d J 7.9 Hz), 7.19 (2H, d J7.9 Hz), 5.80 (1H, br s), 3.61 (3H, s), 2.76 (2H, m), 2.58 (2H, t J 7.7Hz), 2.19 (3H, s), 2.01 (3H, s), 1.80 (3H, m), 1.62-1.51 (m, 4H),1.22-1.11 (4H, m), 0.64 (6H, d J 6.25 Hz). m/z (ES⁺, 70V) 446.2 (MH⁺).

EXAMPLE DDD1000962,6-Dichloro-N-(difluoromethyl)-4-(3-(piperidin-4-yl)propyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamidehydrochloride salt

Prototypical Procedure for Coupling of an Aryl Bromide with a9BBN-Derived Trialkylborane Under Suzuki-Miyaura Conditions;

A solution of tert-butyl 4-allylpiperidine-1-carboxylate (293 mg, 1.29mmol, prepared according to the methods cited by Billote, S. Synlett.,1998, 4, 379-380) in 1.0 ml of THF, under argon at rt, was treateddropwise with 9-BBN (0.5M in THF; 2.6 ml, 1.3 mmol). The reaction wasthen heated in a microwave for 30 min at 90° C. The resulting solutionwas then transferred via cannula into a stirred mixture of the compoundof intermediate 40 (300 mg, 0.645 mmol) and potassium phosphate (272 mg,1.28 mmol) in DMF (2.5 ml) and water (0.75 ml) under argon. Afterbubbling argon through the reaction for 5 min at rt Pd(PPh₃)₄ (20 mg)was added, the reaction vessel sealed and then heated in a microwave at60° C. for 30 min. The reaction mixture was then concentrated in vacuo,diluted with DCM (50 ml) and aqueous ammonia solution (50 ml), theorganic phase separated, washed with brine (2×25 ml), dried (MgSO₄) andconcentrated in vacuo. Chromatography (SiO₂, 4:6 EtOAc:hexanes) gavetert-butyl4-(3-(3,5-dichloro-4-(N-(difluoromethyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfamoyl)phenyl)propyl)piperidine-1-carboxylateas a colourless gum. The above named compound in DCM (10 ml) was treatedwith trifluoroacetic acid (1 ml), stirred at rt for 1 h thenconcentrated in vacuo. The residual gum was diluted with DCM (25 ml) andaqueous ammonia (25 ml), the organic phase separated, dried (MgSO4) andconcentrated. Dilution with DCM (10 ml), treatment with HCl (1 M indiethyl ether, 2 ml) followed by filtration under a stream of argon gavethe title compound as a white hygroscopic powder (210 mg, 0.385 mmol,60%). δH (D₂O, 300K) 7.29 (1H, t J 60.0 Hz), 7.22 (2H, s), 3.40 (3H, s),3.13 (2H, d J 13.2 Hz), 2.68 (2H, t J 11.7 Hz), 2.36 (2H, s br), 1.66(3H, s), 1.61-0.95 (9H, complex), 1.46 (3H, s). m/z (ES⁺, 70V) 509.2(MH⁺).

EXAMPLE DDD1000972,6-dichloro-N-(difluoromethyl)-4-(3-(1-methylpiperidin-4-yl)propyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide

Prepared from 4-allyl-1-methylpiperidine (776 mg, 5.54 mmol) and thecompound of intermediate 40 (2.5 g, 5.4 mmol) according to the method ofcompound DDD100096 to give the title compound as a white powder (2.41 g,4.6 mmol, 85%), δH (D-6 DMSO 300K) 7.36 (1H, t J 59.6 Hz), 7.58 (2H, s),3.64 (3H, s), 3.35 (2H, dm), 3.2-3.0 (1H, m br), 2.86 (2H, m), 2.69 (2H,m), 2.66 (2H, t J 7.5 Hz), 1.88 (3H, s), 1.83 (3H, m), 1.66 (3H, s),1.65-1.57 (2H, m), 1.50-1.39 (2H, m), 1.24-1.17 (2H, m). m/z (ES⁺, 70V)523.2 (MH⁺).

EXAMPLE DDD1001442,6-dichloro-N-(difluoromethyl)-4-(4-(1-methylpiperidin-4-yl)butyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide

Prepared from 4-(but-3-enyl)-1-methylpiperidine (320 mg, 2.14 mmol) andthe compound of intermediate 40 (500 mg, 1.08 mmol) according to themethod of compound DDD100096 to give the title compound as a whitepowder (197 mg, 34%), δH (D-6 DMSO 500K) 10.06 (1H, bs); 7.69 (1H, t, J60 Hz); 7.61 (2H, s); 3.64 (3H, s); 3.36 (2H, m); 2.80 (5H, m); 2.65(2H, m); 1.88 (3H, s); 1.79 (2H, m); 1.59 (3H, s); 1.57 (2H, m); 1.32(7H, m). m/z (ES⁺, 70V) 537.2 (MH⁺).

EXAMPLE DDD1001532,6-dichloro-4-(3-(1-methylpiperidin-4-yl)propyl)-N-(2,2,2-trifluoroethyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide

Prepared from 4-allyl-1-methylpiperidine (448 mg, 3.2 mmol) and thecompound of intermediate 47 (790 mg, 1.6 mmol) according to the methodof DDD100096 to give the title compound as a colourless oil (784 mg,1.41 mmol, 88%). δH (CDCl₃, 300K) 7.20 (2H, s), 4.87-4.73 (1H, m),3.94-3.67 (1H, m), 3.67 (3H, s), 3.29 (2H, brd, J=7.3 Hz), 2.63-2.52(5H, m), 2.40 (2H, brs), 2.18 (3H, s), 1.79 (4H, brd, J=13.5 Hz), 1.61(3H, s), 1.56 (1H, brs), 1.34-1.29 (4H, m). m/z (ES⁺, 70V) 555.1 (MH⁺).

EXAMPLE DDD100798N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-4-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)benzenesulfonamideHydrochloride

Prepared from the boronic ester of intermediate 42 (321 mg, 0.71 mmol),8-Bromo-2,3,4,5-tetrahydro-1H-2-benzazepine (160 mg, 0.71 mmol, preparedaccording to the methods cited by H. Stark et al, Chem Bio Chem, 2004,5, 508-518 and G. L. Grunewald et al, Bioorg. Med. Chem., 9, 2001,1957-1965), tribasic potassium phosphate (150 mg, 0.71 mmol), andPd(PPh₃)₄ (30 mg, 0.026 mmol) in DMF (5 ml) and water (1.5 ml),according to the method of intermediate 11, Dilution with DCM (10 ml),treatment with HCl (1M in diethyl ether, 2 ml) followed by evaporation,trituration with ether and filtration under a stream of argon gave thetitle compound as a white hygroscopic powder (300 mg, 0.61 mmol, 87%).δH (D-6 DMSO, 500K) 9.15 (1H, s), 9.04 (1H, bs), 7.87 (2H, d J 8.6 Hz),7.85 (1H, d J 1.9 Hz), 7.72 (2H, d J 8.6 Hz), 7.68 (1H, dd J 7.9 Hz 1.9Hz), 7.41 (1H, d J 7.9 Hz), 4.41 (2H, m), 3.56 (3H, s), 3.37 (2H, m),3.04 (2H, m), 1.90 (4H, m), 1.77 (3H, s), 1.72 (1H, m), 1.70 (6H, d J6.6 Hz). m/z (ES⁺, 70V) 453.3 (MH⁺).

EXAMPLE 100868N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-4-(2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)benzenesulfonamideHydrochloride

The amine of Example DDD100798 (150 mg, 0.31 mmol) was taken up informic acid (10 ml) and paraformaldehyde (92 mg, 3.10 mmol) added. Thereaction mixture was heated at 85° C. for 18 h then allowed to cool andconcentrated to dryness. The residue was basified with aqueous ammoniasolution (20 ml), extracted with DCM (20 ml) and the organicsconcentrated in vacuo to give a gum which was subjected tochromatography (SiO₂, 94:5:1 DCM: MeOH: saturated aqueous ammoniasolution). Dilution with DCM (10 ml), treatment with HCl (1 M in diethylether, 2 ml) followed by evaporation, trituration with ether andfiltration under a stream of argon gave the title compound as a whitehygroscopic powder (60 mg, 0.12 mmol, 39%). δH (D₂O, 500K) 7.81 (2H, m),7.77 (2H, m), 7.68 (2H, m), 7.42 (1H, m), 4.56 (1H, m), 3.71 (1H, m),3.69 (3H, s), 3.51 (1H, m), 3.08 (2H, m), 2.88 (3H, bs), 2.15 (1H, m),1.98 (3H, s), 1.95 (1H, m), 1.89 (2H, m), 1.64 (1H, m), 0.67 (6H, d J6.7 Hz). m/z (ES⁺, 70V) 467.3 (MH⁺).

Biological Data

TABLE 1 Enzyme and Cellular Activity of N-MyristoyltransferaseInhibitors Enzyme activities are for T. brucei NMT. Where present, Human(HuNMT-1), Aspergillus fumigatus (AfNMT) and Leishmania major (LmNMT)enzyme inhibition data are given in parentheses. Cellular activititesare for inhibition of T. brucei brucei (blood stream form, variant 221).ED₅₀ Reference IC₅₀ (μM) (μM) Number STRUCTURE NMT Enzyme T. brucei MH+DDD16771

4.0  >1 324.1 DDD22988

8.3  >1 377.2 DDD48025

11.8   >1 266.1 DDD60006

16.4   >1 349.1 DDD61393

15.0   >1 401.2 DDD61495

6.4  >1 340.1 DDD64558

2.1  20.0 (HuNMT-1) 21.1 338.1 DDD64750

30.0   >1 326.1 DDD64780

30.0   >1 338.2 DDD71230

3.5  >1 338.2 DDD71231

4.6  >1 293.1 DDD71232

42.0   >1 308.1 DDD71233

2.6  >1 374.2 DDD71234

2.7  >1 350.1 DDD71235

5.4  >1 359.1 DDD71237

8.8  >1 349.2 DDD71238

32.6   >1 291.2 DDD71239

1.0  23.2 335.1 DDD71240

8.0  >1 344.1 DDD71241

1.5  >1 308.2 DDD71242

4.3  >1 322.2 DDD71243

0.50  5.8 350.2 DDD71244

15.9   >1 321.2 DDD71245

5.6  >1 284.1 DDD71246

8.4  >1 316.2 DDD71247

3.4  >1 335.1 DDD71248

62.5   >1 336.2 DDD71250

28.1   >1 291.2 DDD71251

>100      >1 336.1 DDD71252

17.4   >1 368.2 DDD71253

5.6  >1 306.1 DDD71274

2.0  >1 352.2 DDD71275

62.0   >1 354.2 DDD71276

9.5  >1 338.2 DDD71277

95.0   >1 346.1 DDD71278

12.1   >1 363.2 DDD71279

10.0   70.0 (HuNMT-1) >1 321.1 DDD71280

>100      >1 307.1 DDD71281

16.1   >1 337.2 DDD71282

4.0  >1 310.2 DDD71283

7.4  >1 317.1 DDD71284

>100      >1 325.2 DDD71285

19.3   >1 325.2 DDD71286

9.8  >1 296.1 DDD71287

2.8  >1 323.1 DDD71288

>100      >1 307.2 DDD71290

41.0   >1 326.1 DDD71291

>100      >1 320.2 DDD71292

>100      >1 306.1 DDD71293

>100      >1 280.1 DDD71294

4.8  >1 332.1 DDD71295

30.0   >1 308.1 DDD71296

>100      >1 352.2 DDD71297

10.5   >1 342.1 DDD71590

62.0   >1 352.1 DDD71593

3.2  >1 335.1 DDD00071594

9.9  >1 334.1 DDD71600

51.0   >1 347.2 DDD71601

>100      >1 324.2 DDD71607

>100      >1 399.2 DDD71608

>100      >1 338.1 DDD71622

41.0   >1 353.1 DDD71623

42.0   >1 353.1 DDD71630

>100      >1 296.1 DDD71637

11.7   >1 335.2 DDD71644

>100      >1 296.1 DDD71645

>100      >1 348.5 DDD73219

69.0   >1 343.2 DDD73220

2.4  >1 353.1 DDD73221

6.6  >1 354.2 DDD73222

1.0  >1 340.1 DDD73223

1.4  >1 371.1 DDD73224

1.5  >1 438.2 DDD73225

>100      >1 378.1 DDD73226

>100      >1 363.1 DDD73227

0.9  8.1 398.1 DDD73228

13.5   >1 324.2 DDD73229

>100      >1 351.1 DDD73230

10.7   >1 445.1 DDD73231

0.76  6.7 418.2 DDD73232

1.9  18.6 346.2 DDD73233

2.7  >1 373.1 DDD73234

0.55  14.3 413.9 DDD73235

17.0   >1 301.1 DDD73236

11.9   >1 365.1 DDD73237

10.4   >1 412.2 DDD73238

0.63  6.9 405.2 DDD73239

38.7   >50 395.1 DDD73240

1.6  >1 359.1 DDD73241

4.2  >1 344.1 DDD73242

32.0   >1 420.2 DDD73243

5.8  >1 395.2 DDD73262

6.9  >1 450.1 DDD73263

0.92  3.4 441.2 DDD73264

7.0  >1 471.2 DDD73265

22.5   >1 385.2 DDD73266

>100      >1 339.1 DDD73267

44.5   >1 438.2 DDD73268

3.6  >1 400.1 DDD73269

>100      >1 339.1 DDD73271

>100      >1 409.1 DDD73272

35.0   >1 482.1 DDD73273

25.5   >1 483.1 DDD73274

32.2   >1 455.2 DDD73277

40.0   >1 478.1 DDD73278

26.9   >1 461.1 DDD73279

1.1  2.1 453.2 DDD73280

20.7   >1 450.1 DDD73319

1.1  8.4 385.1 DDD73320

2.6  16.3 415.1 DDD73321

4.3  >1 470.1 DDD73322

0.86  5.4 386.1 DDD73323

89.0   >1 495.1 DDD73324

>100      >1 620.1 DDD73325

12.8   >1 440.1 DDD73326

1.4  >1 416.2 DDD73327

2.8  >1 400.2 DDD73328

2.4  19.1 402.2 DDD73329

1.6  >1 402.1 DDD73330

2.3  >1 402.1 DDD73331

6.0  >1 428.2 DDD73332

0.34  3.2 411.1 DDD73333

>100      >1 402.1 DDD73475

0.88  10.5 457.2 DDD73476

0.32  2.3 (HuNMT-1) 4.8 (AfNMT) 1.8 458.1 DDD73477

0.46  6.0 429.2 DDD73478

0.36  4.5 398.1 DDD73479

>100      >1 440.1 DDD73480

4.5  22.1 358.2 DDD73481

6.9  >1 426.1 DDD73482

60.0   >1 462.2 DDD73483

>100      >1 450.1 DDD73484

0.67  3.1 438.1 DDD73485

34.3   >1 434.1 DDD73486

2.8  >1 436.2 DDD73487

1.2  14.2 376.2 DDD73488

0.83  7.9 375.1 DDD73489

12.4   >1 436.2 DDD73490

0.36  4.0 (HuNMT-1) 3.9 (AfNMT) 2.8 427.9 DDD73491

28.4   >1 366.2 DDD73492

13.6   >1 462.1 DDD73493

4.4  >1 453.1 DDD73494

0.71  8.8 452.2 DDD73495

0.96  7.8 400.2 DDD73496

>100      >1 428.1 DDD73497

>100      >1 366.1 DDD73498

0.32  4.3 (HuNMT-1) 14.7 (AfNMT) 2.6 413.2 DDD73499

>100      >1 490.2 DDD73500

2.5  >1 425.1 DDD73501

19.0   >1 461.2 DDD73502

4.8  >1 463.2 DDD73503

2.5  10.5 422.1 DDD73504

4.2  >1 373.1 DDD73505

9.7  >1 413.1 DDD73506

10.0   >1 456.1 DDD73507

4.5  >1 411.2 DDD73508

5.2  >1 448.1 DDD73509

3.8  >1 371.2 DDD73510

26.9   >1 390.1 DDD73511

>100      >1 436.2 DDD73512

6.1  >1 396.1 DDD73513

5.7  >1 401.2 DDD73514

4.7  >1 420.1 DDD73515

1.9  >1 425.2 DDD73516

47.6   >1 438.2 DDD85591

0.59  5.3 452.2 DDD85592

44.0   >1 411.2 DDD85593

0.36  3.5 472.1 DDD85594

3.2  21.0 456.1 DDD85595

66.7   >1 286.2 DDD85596

41.7   >1 411.1 DDD85597

8.0  >1 384.1 DDD85598

18.2   >1 384.1 DDD85599

2.4  >1 402.1 DDD85600

1.9  5.9 482.2 DDD85601

23.3   >1 503.1 DDD85602

0.14  9.5 (HuNMT-1) 2.9 (AfNMT) 0.63 408.2 DDD85603

2.4  >1 477.1 DDD85604

3.3  >1 448.2 DDD85605

0.57  2.4 427.2 DDD85606

4.9  3.6 518.2 DDD85607

1.1  7.1 458.2 DDD85608

18.5   >1 314.2 DDD85609

69.5   >1 444.2 DDD85610

61.6   >1 456.1 DDD85611

7.2  >1 394.2 DDD85612

9.3  >1 454.6 DDD85613

6.6  >1 398.2 DDD85624

0.36  1.5 443.2 DDD85625

0.67  4.6 466.1 DDD85626

0.61  1.9 381.1 DDD85627

0.12  0.62 422.2 DDD85628

11.1   >1 390.1 DDD85629

2.4  38.0 367.2 DDD85630

1.7  >1 451.1 DDD85631

9.3  >1 465.1 DDD85632

57.5   >1 544.2 DDD85633

2.0  >50 390.1 DDD85634

27.9   >1 335.1 DDD85635

11.2   48.1 393.1 DDD85636

75.5   >1 508.1 DDD85637

0.50  3.2 441.1 DDD85638

0.90  >1 453.2 DDD85639

11.7   >1 496.1 DDD85640

3.3  >50 366.1 DDD85641

1.7  16.3 499.1 DDD85642

5.2  >1 401.2 DDD85643

8.0  >1 406.2 DDD85644

1.3  2.1 521.2 DDD85645

0.36  0.23 495.2 DDD85646

0.001 0.003 (HuNMT-1) 0.009 (NWT) 0.001 496.1 DDD85647

66.1   >1 381.1 DDD85648

47.7   >1 436.2 DDD85649

40.0   >1 422.1 DDD85650

52.6   >1 395.1 DDD85651

1.8  9.8 469.2 DDD86206

0.001 0.003 (HuNMT-1) 0.001 461.2 DDD86208

3.5  >1 379.9 DDD86209

1.0  >1 447.0 DDD86210

6.0  >1 370.2 DDD86211

0.69  0.19 509.1 DDD86212

0.011 0.008 (HuNMT-1 ) 0.015 (AfNMT) 0.03 453.1 DDD86213

0.001 0.007 (HuNMT-1) 0.01 (AfNMT) 0.003 426.1 DDD86291

1.0  >1 484.9 DDD86292

1.0  >1 523.2 DDD86293

1.0  >1 326.2 DDD86294

1.0  >1 441.9 DDD86295

1.0  >1 498.1 DDD86296

1.2  >1 350.1 DDD86297

1.0  >1 483.1 DDD86298

1.0  >1 436.1 DD86299

1.0  >1 498.2 DDD86300

0.07  1.73 435.1 DDD86301

1.0  >1 469.1 DDD86302

1.0  >1 546.1 DDD86303

1.0  >1 469.2 DDD86304

1.0  >1 484.1 DDD86305

0.87  >1 393.1 DDD86306

1.0  >1 378.2 DDD86307

1.0  >1 339.1 DDD86308

1.0  >1 534.1 DDD86309

1.0  >1 497.1 DDD86310

1.0  >1 494.2 DDD86311

1.0  >1 400.2 DDD86312

0.03  0.07 427.2 DDD86314

1.0  >1 441.1 DDD86315

1.0  >1 540.1 DDD86316

0.61  5.0 442.1 DDD86317

0.01  0.02 440.1 DDD86318

0.08  0.21 425.1 DDD86467

0.01  0.003 537.2 DDD86468

0.01  0.20 482.1 DDD86469

0.17  0.55 470.2 DDD86470

0.01  0.02 (HuNMT-1) 0.007 (AfNMT) 0.02 493.1 DDD86471

0.01  0.009 413.2 DDD86472

10.0   >1 483.2 DDD86473

10.0   >1 523.2 DDD86474

0.07  0.65 399.2 DDD86475

0.001 0.01 (HuNMT-1) 0.003 481.1 DDD86476

5.9  >1 455.2 DDD86477

7.2  >1 418.2 DDD86478

0.04  0.06 (HuNMT-1) 0.24 467.1 DDD86479

0.01  0.016 (HuNMT-1) 0.005 494.1 DDD86480

0.02  0.08 (HuNMT-1) 0.33 478.1 DDD86481

0.001 0.003 (HuNMT-1) 0.002 537.2 DDD87748

0.001 0.008 (HuNMT- 1) 0.001 441.2 DDD87749

0.79  9.3 (HuNMT-1) 9.3 (AfNMT) 1.28 426.2 DDD87751

5.0  >1 386.2 DDD87753

0.23  0.18 (HuNMT-1) 0.80 (AfNMT) >1 464.1 DDD87754

0.34  1.6 515.2 DDD87765

0.05  0.98 485.2 DDD87756

0.76  >1 503.1 DDD87757

0.003 0.01 (HuNMT-1) 0.09 (AfNMT) 0.003 434.2 DDD87758

40.1   >1 427.2 DDD87759

0.91  >1 454.1 DDD87760

34.4   >1 510.2 DDD87761

0.01  0.04 (HuNMT-1) 0.11 (AfNMT) 0.02 455.2 DDD87762

2.6  >1 465.1 DDD87763

0.003 0.02 (HuNMT-1) 0.003 441.2 DDD87764

0.97  >1 454.1 DDD87765

2.8  >1 461.1 DDD87766

10.0   >1 404.1 DDD87767

0.002 0.008 (HuNMT-1) 0.008 (AfNMT) 0.003 441.2 DDD87768

0.01  0.06 425.2 DDD87769

0.003 0.27 (AfNMT) 0.008 474.1 DDD87993

0.005 0.009 (HuNMT- 1) 0.01 481.1 DDD87994

0.01  0.23 (AfNMT) 0.11 410.2 DDD87995

0.06  0.02 413.2 DDD87997

0.03  0.013 (HuNMT-1) 0.02 (AfNMT) 0.003 463.2 DDD87999

0.21  >1 402.1 DDD88000

0.03  1.5 (AfNMT) 0.77 407.2 DDD88002

0.02  0.65 (HuNMT-1) 0.79 (AfNMT) 0.14 482.1 DDD88003

0.16  1.9 408.2 DDD88004

6.2  >1 380.0 DDD88005

0.23  0.1 399.3 DDD88006

0.35  4.2 (AfNMT) 3.9 422.2 DDD88007

0.02  0.13 (HuNMT-1) 0.14 (AfNMT) 0.08 495.1 DDD88008

0.11  18.0 420.2 DDD88009

0.02  0.10 493.1 DDD88186

0.003 0.006 (HuNMT-1) 0.003 441.2 DDD88187

0.37  2.15 512.2 DDD88188

0.003 0.009 (HuNMT-1) 0.005 445.2 DDD88189

0.43  >1 412.2 DDD88190

1.1  31.0 393.1 DDD88191

0.12  10.0 (AfNMT) 0.67 406.2 DDD88193

0.003 0.005 (HuNMT-1) 0.007 (AfNMT) 0.005 509.1 DDD88194

0.48  2.0 512.2 DDD88195

0.05  0.51 441.2 DDD88196

0.02  0.017 (HuNMT-1) 0.035 (AfNMT) 0.05 468.2 DDD88197

13.8   45.9 456.0 DDD88198

0.71  2.3 456.0 DDD88315

20.0   70.8 (HuNMT-1) >10 399.9 DDD88316

12.7   107 (HuNMT-1) >10 358.0 DDD88317

10.0   >100 (HuNMT-1) >10 379.0 DDD88318

10.0   87.0 (HuNMT-1) >10 362.0 DDD88319

0.045 0.77 (HuNMT-1) 0.69 492.1 DDD88320

44.1   >100 (HuNMT-1) >10 330.0 DDD88321

>100      >100 (HuNMT-1) >10 316.0 DDD88322

0.182 1.5 (HuNMT-1) 1.93 478.1 DDD88323

0.004 0.29 (HuNMT-1) 0.005 463.2 DDD88324

75.4   3.36 (HuNMT-1) >10 399.9 DDD88325

>100      >100 (HuNMT-1) >10 385.9 DDD88326

>100      >100 (HuNMT-1) >10 330.0 DDD88523

0.61  6.3 (HuNMT-1) >1 415.2 DDD88533

5.98  17.7 (HuNMT-1) >10 351.1 DDD88549

0.025 0.24 (HuNMT-1) 0.11 468.2 DDD88557

0.002 0.301 (HuNMT-1) 0.001 (LmNMT) 0.002 472.2 DDD88558

0.006 0.007 (HuNMT-1) 0.009 522.1 DDD88559

0.008 0.175 (HuNMT-1) 0.038 405.2 DDD88560

0.054 0.272 (HuNMT-1) 2.15 371.1 DDD88580

0.077 1.0 (HuNMT-1) 1.13 391.2 DDD88636

0.92  3.7 (HuNMT-1) 1.89 537.2 DDD88638

0.009 0.047 (HuNMT-1) 0.084 469.3 DDD88640

>1     >1 (HuNMT-1) 18.7 406.2 DDD88641

0.029 0.31 (HuNMT-1) 0.31 509.2 DDD88642

0.39 4.48 (HuNMT-1) 0.89 535.2 DDD88643

0.063 0.144 (HuNMT-1) 0.49 483.3 DDD88644

0.003 0.188 (HuNMT-1) 0.012 488.2 DDD88645

0.003 0.021 (HuNMT-1) 0.021 509.2 DDD88646

0.002 0.003 (HuNMT-1) 0.002 523.2 DDD90022

0.002 0.004 (HuNMT-1) 0.002 473.2 DDD90023

0.016 0.397 (HuNMT-1) 0.20 419.2 DDD90057

0.085 0.075 (HuNMT-1) 0.73 536.2 DDD90058

0.027 0.740 (HuNMT-1) 0.20 440.2 DDD90059

0.054 0.548 (HuNMT-1) 0.48 442.2 DDD90060

0.006 0.180 (HuNMT-1) 0.02 516.2 DDD90086

0.004 0.01 (HuNMT-1) 0.006 501.2 DDD90091

0.009 0.009 (HuNMT-1) 0.063 467.2 DDD90098

0.008 0.047 (HuNMT-1) 0.060 453.2 DDD90106

0.024 0.064 (HuNMT-1) 0.251 413.2 DDD90107

0.004 0.005 (HuNMT-1) 0.040 453.2 DDD90111

0.003 0.019 (HuNMT-1) 0.005 491.2 DDD90112

0.017 0.164 (HuNMT-1) 0.270 405.2 DDD90115

0.260 6.1 (HuNMT-1) 2.21 420.1 DDD90118

0.004 0.005 (HuNMT-1) 0.015 536.2 DDD90142

0.012 0.234 (HuNMT-1) 0.168 461.3 DDD90143

0.082 1.37 (HuNMT-1) 0.81 462.3 DDD90144

0.006 0.088 (HuNMT-1) 0.034 433.3 DDD90145

0.09  0.76 (HuNMT-1) 1.00 393.2 DDD90146

0.002 0.018 (HuNMT-1) 0.002 487.2 DDD90147

0.034 0.939 (HuNMT-1) 0.20 448.3 DDD90152

0.50  >1 (HuNMT-1) >1 495.3 DDD90153

0.31  >1 (HuNMT-1) >1 447.3 DDD90154

0.003 0.352 (HuNMT-1) 0.023 502.5 DDD90155

>1     >1 (HuNMT-1) 4.0 459.3 DDD99735

0.83  2.9 (HuNMT-1) >1 416.2 DDD99736

0.068 0.25 (HuNMT-1) 0.41 496.3 DDD99739

0.005 0.12 (HuNMT-1) 0.058 467.3 DDD99741

0.005 0.021 (HuNMT-1) 0.047 455.3 DDD99742

0.003 0.015 (HuNMT-1) 0.035 (LmNMT) 0.019 441.3 DDD99743

0.003 0.016 (HuNMT-1) 0.005 515.3 DDD99745

2.1  >10 (HuNMT-1) >1 379.3 DDD99746

2.0  >10 (HuNMT-1) >1 402.3 DDD99747

0.008 0.81 (HuNMT-1) 0.067 537.2 DDD99748

0.006 0.019 (HuNMT-1) 0.036 427.2 DDD99749

0.45  >1 (HuNMT-1) >1 365.3 DDD99750

>1     >1 (HuNMT-1) >1 388.3 DDD99751

0.003 0.141 (HuNMT-1) 0.021 502.2 DDD99752

0.003 0.051 (HuNMT-1) 0.019 474.2 DDD99753

0.029 0.076 (HuNMT-1) 0.406 407.3 DDD99754

0.105 2.1 (HuNMT-1) >1 (AfNMT) >1 430.3 DDD99755

0.003 0.011 (HuNMT-1) 0.002 488.2 DDD99756

0.011 0.98 (HuNMT-1) 0.121 343.3 DDD099757

0.006 0.054 (HuNMT-1) 0.061 467.3 DDD99758

0.009 0.127 (HuNMT-1) 0.110 391.3 DDD99759

0.002 0.008 (HuNMT-1) 0.003 459.0 DDD99760

0.005 0.029 (HuNMT-1) 0.010 405.3 DDD99761

0.028 0.250 (HuNMT-1) 0.240 415.3 DDD99763

0.007 0.058 (HuNMT-1) 0.053 503.3 DDD99815

0.025 0.19 (HuNMT-1) 0.123 481.3 DDD99816

0.016 0.153 (HuNMT-1) 0.031 459.2 DDD99817

0.014 0.56 (HuNMT-1) 0.047 455.2 DDD99818

0.011 0.85 (HuNMT-1) 0.047 448.3 DDD99819

0.008 0.041 (HuNMT-1) 0.043 455.2 DDD99820

0.005 0.052 (HuNMT-1) 0.020 421.2 DDD99821

0.16  3.8 (HuNMT-1) 0.59 510.3 DDD99822

0.006 0.017 (HuNMT-1) 0.051 509.3 DDD99823

0.006 0.033 (HuNMT-1) 0.041 475.3 DDD99824

0.004 0.013 (HuNMT-1) 0.014 455.2 DDD99825

0.011 0.036 (HuNMT-1) 0.039 (LmNMT) 0.054 421.3 DDD99826

0.016 0.094 (HuNMT-1) 0.104 475.2 DDD99827

0.007 0.029 (HuNMT-1) 0.019 459.2 DDD99830

0.003 0.032 (HuNMT-1) 0.011 (LmNMT) 0.020 419.3 DDD99832

0.003 0.011 (HuNMT-1) 0.044 (AfNMT) 0.010 459.2 DDD99833

0.003 0.168 (HuNMT-1) 0.009 (LmNMT) 0.018 498.2 DDD99834

0.019 0.47 (HuNMT-1) 0.225 484.2 DDD99835

0.38  >1 (HuNMT-1) >1 442.0 DDD99836

0.003 0.15 (HuNMT-1) 0.013 516.2 DDD99837

0.007 0.12 (HuNMT-1) 0.20 (AfNMT) 0.036 447.3 DDD99838

0.17  0.37 (HuNMT-1) >1 444.25 DDD100086

0.003 0.145 (HuNMT-1) 0.012 524.2 DDD100088

0.002 0.024 (HuNMT-1) 0.003 501.2 DDD100091

0.002 0.009 (HuNMT-1) 0.004 487.2 DDD100093

0.162 0.021 (HuNMT-1) 0.106 435.3 DDD100094

0.003 0.025 (HuNMT-1) 0.008 481.3 DDD100095

0.005 0.022 (HuNMT-1) 0.055 441.3 DDD100096

0.003 0.009 (HuNMT-1) 0.003 509.2 DDD100097

0.002 0.021 (HuNMT-1) 0.001 523.2 DDD100139

1.4  2.3 (HuNMT-1) >1 517.3 DDD100140

0.12  0.74 (HuNMT-1) >1 525.3 DDD100141

0.003 0.033 (HuNMT-1) 0.003 (LmNMT) 0.003 537.2 DDD100142

0.004 0.081 (HuNMT-1) 0.014 538.0 DDD100143

0.003 0.01 (HuNMT-1) 0.017 475.2 DDD100144

0.002 0.006 (HuNMT-1) 0.001 (LmNMT) 0.001 537.0 DDD100145

0.011 0.148 (HuNMT-1) 0.035 (LmNMT) 0.02 523.2 DDD100146

0.36  2.3 (HuNMT-1) >1 481.3 DDD100147

3.2  >10 (HuNMT-1) >1 477.9 DDD100148

0.008 0.21 (HuNMT-1) 0.018 558.2 DDD100149

0.014 2.4 (HuNMT-1) 0.132 556.2 DDD100150

1.3  4.0 (HuNMT-1) >1 503.3 DDD100151

0.011 0.134 (HuNMT-1) 0.034 541.1 DDD100153

0.005 0.323 (HuNMT-1) 0.023 555.2 DDD100156

0.016 1.1 (HuNMT-1) 0.048 (LmNMT) 0.148 534.2 DDD100157

0.006 0.21 (HuNMT-1) 0.014 570.2 DDD100158

0.006 0.056 (HuNMT-1) 0.048 447.0 DDD100159

0.004 0.06 (HuNMT-1) 0.009 551.0 DDD100160

0.003 0.345 (HuNMT-1) 0.013 537.0 DDD100161

0.002 0.034 (HuNMT-1) 0.006 553.0 DDD100162

0.01  0.173 (HuNMT-1) 0.093 461.4 DDD100163

0.014 1.7 (HuNMT-1) 0.125 538.2 DDD100164

0.002 0.007 (HuNMT-1) 0.005 (LmNMT) 0.001 538.2 DDD100165

0.004 0.11 (HuNMT-1) 0.020 569.2 DDD100166

0.005 0.008 (HuNMT-1) 0.002 524.2 DDD100167

0.004 0.071 (HuNMT-1) 0.014 555.2 DDD100168

0.009 0.168 (HuNMT-1) 0.110 463.2 DDD100169

0.003 0.005 (HuNMT-1) 0.001 (LmNMT) 0.001 539.1 DDD100790

0.043 0.52 (HuNMT-1) 0.35 (LmNMT) 0.269 495.3 DDD100791

0.21  2.1 (HuNMT-1) 0.044 (LmNMT) 0.344 576.2 DDD100792

0.01  0.076 (HuNMT-1) 0.23 (LmNMT) 0.143 481.3 DDD100793

0.026 0.33 (HuNMT-1) 1.4 (LmNMT) 0.54 504.3 DDD100794

0.013 0.49 (HuNMT-1) 0.024 (LmNMT) 0.160 562.2 DDD100795

0.003 0.042 (HuNMT-1) 0.002 (LmNMT) 0.005 548.2 DDD100796

0.86  >1 (HuNMT-1) >1 (LmNMT) >1 518.3 DDD100797

0.023 0.077 (HuNMT-1) 0.27 (LmNMT) 0.492 471.3 DDD100798

0.003 0.004 (HuNMT-1) 0.025 (LmNMT) 0.006 453.3 DDD100799

0.02  0.24 (HuNMT-1) 0.47 (LmNMT) 0.293 455.3 DDD100800

0.006 0.021 (HuNMT-1) 0.073 (LmNMT) 0.052 455.3 DDD100801

0.004 0.011 (HuNMT-1) 0.011 (LmNMT) 0.014 439.2 DDD100802

0.003 0.101 (HuNMT-1) 0.005 (LmNMT) 0.004 552.0 DDD100803

0.002 0.046 (HuNMT-1) 0.005 (LmNMT) 0.008 571.2 DDD100804

0.006 0.061 (HuNMT-1) 0.077 (LmNMT) 0.035 481.3 DDD100805

0.27  >1 (HuNMT-1) >1 (LmNMT) >1 463.2 DDD100806

0.004 0.057 (HuNMT-1) 0.224 (LmNMT) 0.033 485.3 DDD100807

0.002 0.004 (HuNMT-1) 0.001 (LmNMT) 0.001 523.2 DDD100862

0.358 0.174 (HuNMT-1) >1 μM (LmNMT) >1 μM 441.2 DDD100863

0.006 0.051 (HuNMT-1) 0.091 (LmNMT) 0.015 469.3 DDD100865

0.097 0.314 (HuNMT-1) 1.9 (LmNMT) 7.3 441.2 DDD100866

0.010 0.047 (HuNMT-1) 0.054 (LmNMT) 3.2 441.2 DDD100867

0.006 0.039 (HuNMT-1) 0.074 (LmNMT) 0.048 427.2 DDD100868

0.015 0.002 (HuNMT-1) 0.004 (LmNMT) 0.0009 467.3 DDD100869

0.004 0.006 (HuNMT-1) 0.019 (LmNMT) 5.7 518.3 DDD100870

0.005 0.018 (HuNMT-1) 0.045 (LmNMT) 0.013 441.2 DDD100871

7.95  >1 μM (HuNMT-1) >1 μM (LmNMT) 51.0 374.0 DDD100872

0.003 0.017 (HuNMT-1) 0.005 (LmNMT) 0.002 551.2 DDD100873

13.8   >1 μM (HuNMT-1) >1 μM (LmNMT) >1 μM 422.2 DDD100874

0.740 >1 μM (HuNMT-1) >1 μM (LmNMT) >1 μM 422.2 DDD100875

2.68  >1 μM (HuNMT-1) >1 μM (LmNMT) 20.5 386.1 DDD100876

0.006 0.020 (HuNMT-1) 0.059 (LmNMT) 0.014 453.3 DDD100877

123.0   >1 μM (HuNMT-1) >1 μM (LmNMT) 33.9 420.0 DDD100878

0.262 2.4 (HuNMT-1) 0.906 (LmNMT) >1 μM 422.2 DDD100879

0.803 2.6 (HuNMT-1) 1.59 (LmNMT) >1 μM 408.2 DDD100880

>1 μM >1 μM (HuNMT-1) >1 μM (LmNMT) 21.4 436.0 DDD100881

0.020 0.233 (HuNMT-1) 0.778 (LmNMT) 0.234 481.3 DDD100882

0.305 0.769 (HuNMT-1) >1 μM (LmNMT) 2.45 518.3 DDD100883

0.023 >1 μM (HuNMT-1) 0.672 (LmNMT) 0.427 495.3 DDD100884

1.08  >1 μM (HuNMT-1) >1 μM (LmNMT) >1 μM 408.2 DDD100885

0.032 0.096 (HuNMT-1) 0.211 (LmNMT) 9.72 489.2 DDD100886

0.016 0.019 (HuNMT-1) 0.16 (LmNMT) 0.004 587.2 DDD100887

0.010 0.018 (HuNMT-1) 0.005 (LmNMT) 0.005 545.1 DDD100888

0.004 0.012 (HuNMT-1) 0.005 (LmNMT) 0.003 477.2 DDD100889

5.3  1.3 (HuNMT-1) 1.2 (LmNMT) >1 μM 506.0 DDD100891

0.020 0.100 (HuNMT-1) 0.045 (LmNMT) 0.129 474.2 DDD100965

0.025 0.037 (HuNMT-1) 0.026 (LmNMT) nd 452.2 DDD100966

0.012 0.22 (HuNMT-1) 0.012 (LmNMT) nd 432.2 DDD100968

0.016 0.14 (HuNMT-1) 0.045 (LmNMT) nd 446.2 DDD100969

0.010 0.019 (HuNMT-1) 0.044 (LmNMT) nd 438.2 DDD100971

0.04  0.63 (HuNMT-1) 0.55 (LmNMT) nd 494.2 DDD100972

0.005 0.014 (HuNMT-1) 0.005 (LmNMT) nd 446.2 DDD100974

0.026 0.11 (HuNMT-1) 0.028 (LmNMT) nd 474.2 DDD100978

0.019 >1.0 (HuNMT-1) 0.04 (LmNMT) nd 594.2 DDD100979

0.20  0.20 (HuNMT-1) >1.0 (LmNMT) nd 454.2 DDD100980

0.028 0.15 (HuNMT-1) 0.13 (LmNMT) nd 444.2 DDD100985

0.10  0.62 (HuNMT-1) 0.38 (LmNMT) nd 460.2 DDD100986

0.018 0.33 (HuNMT-1) 0.16 (LmNMT) nd 446.2 DDD100990

0.024 0.40 (HuNMT-1) 0.13 (LmNMT) nd 460.2 DDD100991

0.005 0.03 (HuNMT-1) 0.05 (LmNMT) nd 494.2

TABLE 2 Activity of N-Myristoyltransferase Inhibitors Against HumanCancer Cell Lines IC₅₀ (μM) Reference HT29 HCT116 SkBr3 RT112 C6 H460MRC5 HT1080 A549 DDD85646 0.112 0.234 0.108 0.330 1.16 1.32 0.123 0.060.157 DDD86206 0.154 0.422 0.141 0.425 1.89 2.53 0.209 0.086 0.213

TABLE 3 Activity of N-Myristoyltransferase Inhibitors Against HumanCancer Cell Lines IC₅₀(μM) Reference NCI-H1299 MDA-MB-231 OE19 OE21DDD85646 0.57 0.23 0.66 0.29 DDD86212 1.08 0.64 4.37 1.39 DDD86470 3.710.89 4.57 1.20 DDD86481 0.096 0.047 0.132 0.057

TABLE 4 Activity of N-Myristoyltransferase Inhibitors Against HumanCancer Cell Lines IC₅₀(μM) Reference MDA-MB-231 HT-29 HCT116 DDD856460.23 0.112 0.234 DDD88558 0.448 0.176 0.629 DDD90086 0.537 0.281 0.921DDD90149 2.23 >10 1.91 DDD100144 0.218 n.d. 0.282 DDD100169 0.249 n.d.0.419

Assessment of the CNS penetration of NMT inhibitors was determined inthe female NMRI mouse following i.v. dosing (n=3 per dose group,concentration measured after t=5 min).

TABLE 5 Drug concentration in blood and brain in the female NMRI mouseat t = 5 min following single i.v. dosing (average of three animals)Conc (ng/ml Conc (ng/ml Reference Dose in blood) in brain) Brain:BloodDDD73490 0.33 mg/kg 52 314 6.0 DDD88195  1.0 mg/kg 116 93 0.8 DDD88638 2.0 mg/kg 281 378 1.35 DDD90154  2.0 mg/kg 455 608 1.34 DDD99742  2.0mg/kg 642 422 0.66 DDD99837  3.0 mg/kg 388 99 0.26 DDD100097  2.0 mg/kg224 335 1.50 DDD100144  2.0 mg/kg 413 545 1.32 DDD100153  2.0 mg/kg 269171 0.64

Assessment of the antitrypanosomal efficacy of DDD85646 in an acutemodel of trypanosomiasis was determined at six dose levels in the femaleNMRI mouse (n=3 per dose group). Compound was dosed for four days b.i.d.at the stated level, commencing three days after infection with 1×10⁴trypanosomes (T. brucei brucei, blood stream form, variant 221).

1-60. (canceled)
 61. A compound of formula (III)

wherein n is 0, 1, 2, 3, 4, 5 or 6; ring B is an optionally substituted5 or 6-membered aryl or heteroaryl group wherein each substitutablecarbon or heteroatom in Ring B is optionally and independentlysubstituted by one or more R³; W is selected from a hydrocarbyloptionally substituted with R¹¹, an optionally substituted aryl orheteroaryl group and a carbocyclyl optionally substituted with one ormore of halogen, cyano, amino, hydroxy, C₁₋₆ alkyl and C₁₋₆ alkoxygroups; X is selected from a hydrocarbyl optionally substituted with R¹¹and a carbocyclyl optionally substituted with one or more of halogen,cyano, amino, hydroxy, C₁₋₆ alkyl and C₁₋₆ alkoxy groups; wherein one ofW and X may be absent; R¹, R², R³, R⁴ and R⁵ are independently selectedfrom hydrogen, R¹², hydrocarbyl optionally substituted with R¹², and—(CH₂)_(l)-heterocyclyl optionally substituted with R¹²; wherein R¹ andR² taken together with the atoms to which they are attached may form aheterocycle, optionally substituted with one or more R¹²; wherein R¹and/or R² taken together with W or X may form a heterocycle optionallysubstituted with one or more R¹²; and wherein one or more of R³ and R⁵taken together with the atoms to which they are attached may form acarbocycle, for example heterocyclyl, optionally substituted with R¹²; lis 0, 1, 2, 3, 4, 5 or 6; wherein each R¹¹ and R¹² is independentlyselected from halogen, trifluoromethyl, cyano, thio, nitro, oxo, ═NR¹³,—OR¹³, —SR¹³, —C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³, —NR¹³COR¹⁴, —NR¹³CONR¹³ ₂,—NR¹³COR¹⁴, —NR¹³CO₂R¹⁴, —S(O)R¹³, —S(O)₂R¹³, —SONR¹³ ₂, —NR¹³S(O)₂R¹⁴;—CSR¹³, —N(R¹³)R¹⁴, —C(O)N(R¹³)R¹⁴, —SO₂N(R¹³)R¹⁴ and R¹⁵; wherein R¹³and R¹⁴ are each independently selected from hydrogen or R¹⁵; whereinR¹⁵ is selected from hydrocarbyl, carbocyclyl and—(CH₂)_(m)-heterocyclyl, and each R¹⁵ is optionally and independentlysubstituted with one or more of halogen, cyano, amino, hydroxy, C₁₋₆alkyl and C₁₋₆ alkoxy; m is 0, 1, 2, 3, 4, 5 or 6; p is 0, 1, 2, 3 or 4;wherein the values of R⁴ may be the same or different; q is 0, 1, 2, 3or 4; wherein the values of R⁵ may be the same or different; Y and Z,one or both of which may be absent, are independently selected fromhydrogen, R¹⁶, hydrocarbyl optionally substituted with R¹⁶, and—(CH₂)_(r)-heterocyclyl optionally substituted with R¹⁶, wherein eachR¹⁶ is independently selected from halogen, trifluoromethyl, cyano,thio, nitro, oxo, ═NR¹⁷, —OR¹⁷, —SR¹⁷, —C(O)R¹⁷, —C(O)OR¹⁷, —OC(O)R¹⁷,—NR¹⁷COR¹⁸, —NR¹⁷CONR¹⁸ ₂, —NR¹⁷COR¹⁸, —NR¹⁷CO₂R¹⁸, —S(O)R¹⁷, —S(O)₂R¹⁷,—SONR¹⁷ ₂, —NR¹⁷S(O)₂R¹⁸; —CSR¹⁷, —N(R¹⁷)R¹⁸, —C(O)N(R¹⁷)R¹⁸,—SO₂N(R¹⁷)R¹⁸ and R¹⁹; r is 0, 1, 2, 3, 4, 5 or 6; wherein R¹⁷ and R¹⁸are each independently selected from hydrogen or R¹⁹; wherein R¹⁹ isselected from hydrocarbyl, carbocyclyl and —(CH₂)_(s)-heterocyclyl, andeach R¹⁹ is optionally and independently substituted with one or more ofhalogen, cyano, amino, hydroxy, C₁₋₆ alkyl and C₁₋₆ alkoxy; s is 0, 1,2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt thereof.
 62. Acompound as claimed in claim 61 wherein ring B is a 6 membered arylgroup.
 63. A compound as claimed in claim 61 wherein n is
 0. 64. Acompound as claimed in claim 61 wherein the compound is of formula (V):

wherein t is 0, 1, 2, 3, 4, 5 or 6; ring D is an optionally substitutednitrogen containing 6 or 7 membered heterocycle, for example piperidine,wherein each substitutable carbon or nitrogen in Ring D is optionallyand independently substituted by one or more R⁷; R⁷ is independentlyselected from hydrogen, R²⁰, hydrocarbyl (e.g. C₁₋₆ alkyl, alkenyl,alkynyl, or haloalkyl) optionally substituted with R²⁰, and—(CH₂)_(v)-heterocyclyl optionally substituted with R²⁰: v is 0, 1, 2,3, 4, 5 or 6; wherein each R²⁰ is independently selected from halogen,trifluoromethyl, cyano, thio, nitro, oxo, ═NR²¹, —OR²¹, —SR²¹, —C(O)R²¹,—C(O)OR²¹, —OC(O)R²¹, —NR²¹COR²², —NR²¹CONR²² ₂, —NR²¹COR²²,—NR²¹CO₂R²², —S(O)R²¹, —S(O)₂R²¹, —SONR²¹ ₂, —NR²¹S(O)₂R²²; —CSR²¹,N(R²¹)R²², —C(O)N(R²¹)R²², —SO₂N(R²¹)R²² and R²³; wherein R²¹ and R²²are each independently selected from hydrogen or R²³; wherein R²³ isselected from hydrocarbyl (e.g. C₁₋₆ alkyl, alkenyl, alkynyl, orhaloalkyl), carbocyclyl and —(CH₂)_(w)-heterocyclyl, and each R²³ isoptionally and independently substituted with one or more of halogen,cyano, amino, hydroxy, C₁₋₆ alkyl and C₁₋₆ alkoxy; w is 0, 1, 2, 3, 4, 5or 6; R⁸ is selected from the list of optional substituents representedby the group R⁴.
 65. A compound as claimed in claim 64 having thestructure:

wherein n′ is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and E is independentlyselected from E and N.
 66. A compound as claimed in claim 65 wherein Eis C.
 67. A compound as claimed in claim 61 having the structure:

wherein R^(5a), R^(5b) and R^(5c) are independently selected fromhydrogen, R¹², hydrocarbyl (e.g. C₁₋₆ alkyl, alkenyl, alkynyl, orhaloalkyl) optionally substituted with R¹², and —(CH₂)_(l)-heterocyclyloptionally substituted with R¹²; wherein R^(3a) and R^(3b) areindependently selected from hydrogen, R¹², hydrocarbyl (e.g. C₁₋₆ alkyl,alkenyl, alkynyl, or haloalkyl) optionally substituted with R¹², and—(CH₂)_(l)-heterocyclyl optionally substituted with R¹².
 68. A compoundas claimed in claim 67 wherein R^(5a), R^(5b) and R^(5c) independentlyrepresent C₁₋₆ alkyl.
 69. A compound as claimed in claim 61 having thestructure:


70. A compound as claimed in claim 61 wherein W is C₁₋₆ alkyl orcycloalkyl.
 71. A compound as claimed in claim 64 having the structure:

wherein u is 0, 1, 2, 3, 4, 5 or 6; ring C is an optionally substitutedcyclic group wherein each substitutable carbon or heteroatom in Ring Cis optionally and independently substituted by one or more R⁶; R⁶ isindependently selected from hydrogen, R²⁰, hydrocarbyl (e.g. C₁₋₆ alkyl,alkenyl, alkynyl, or haloalkyl) optionally substituted with R²⁰, and—(CH₂)_(v)-heterocyclyl optionally substituted with R²⁰; v is 0, 1, 2,3, 4, 5 or 6; wherein each R²⁰ is independently selected from halogen,trifluoromethyl, cyano, thio, nitro, oxo, ═NR²¹, —OR²¹, —SR²¹, —C(O)R²¹,—C(O)OR²¹, —OC(O)R²¹, —S(O)R²¹, —S(O)₂R²¹, —N(R²¹)R²², —C(O)N(R²¹)R²²,—SO₂N(R²¹)R²² and R²³; wherein R²¹ and R²² are each independentlyselected from hydrogen or R²³; wherein R²³ is selected from hydrocarbyl(e.g. C₁₋₆ alkyl, alkenyl, alkynyl, or haloalkyl), carbocyclyl and—(CH₂)_(w)-heterocyclyl, and each R²³ is optionally and independentlysubstituted with one or more of halogen, cyano, amino, hydroxy, C₁₋₆alkyl and C₁₋₆ alkoxy; w is 0, 1, 2, 3, 4, 5 or
 6. 72. A compound asclaimed in claim 71 wherein Ring C is an aryl group.
 73. A compound asclaimed in claim 71 wherein Ring C is a phenyl group.
 74. A compound asclaimed in claim 71 having the structure:


75. A compound as claimed in claim 61 wherein R⁴ is selected fromhydrogen or C₁₋₆ alkyl optionally substituted with halogen, inparticular fluoro.
 76. A compound as claimed in claim 61 selected fromthe group consisting of